Journal of Alzheimer's Disease Reports - Volume 7, issue 1

Authors: Tolea, Magdalena I. | Camacho, Simone | Cohen, Iris R. | Galvin, James E.

Article Type: Research Article

Abstract: Background: Greater mindfulness, the practice of awareness and living in the moment without judgement, has been linked to positive caregiving outcomes in dementia caregivers and its impact attributed to greater decentering and emotion regulation abilities. Whether the impact of these mindfulness-based processes varies across caregiver subgroups is unclear. Objective: Analyze cross-sectional associations between mindfulness and caregiver psychosocial outcomes, considering different caregiver and patient characteristics. Methods: A total of 128 family caregivers of persons living with Alzheimer’s disease and related disorders were assessed on several mindfulness measures (i.e., global; decentering, positive emotion regulation, negative emotion regulation) and …provided self-reported appraisals of caregiving experience; care preparedness; confidence, burden, and depression/anxiety. Bivariate relationships between mindfulness and caregiver outcomes were assessed with Pearson’s correlations and stratified by caregiver (women versus men; spouse versus adult child) and patient (mild cognitive impairment (MCI) versus Dementia; AD versus dementia with Lewy bodies; low versus high symptom severity) characteristics. Results: Greater mindfulness was associated with positive outcomes and inversely associated with negative outcomes. Stratification identified specific patterns of associations across caregiver groups. Significant correlations were found between all mindfulness measures and caregiving outcomes in male and MCI caregivers while the individual mindfulness component of positive emotion regulation was significantly correlated to outcomes in most caregiver groups. Conclusion: Our findings support a link between caregiver mindfulness and improved caregiving outcomes and suggest directions of inquiry into whether the effectiveness of dementia caregiver-support interventions may be improved by targeting specific mindfulness processes or offering a more inclusive all-scope approach depending on individual caregiver or patient characteristics. Show more

Keywords: Caregiver burden, caregivers, dementia, emotional regulation, informal care, mindfulness

DOI: 10.3233/ADR-220069

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 151-164, 2023

Authors: Roberts, Blaine R. | Laffoon, Scott B. | Roberts, Anne M. | Porter, Tenielle | Fowler, Chris | Masters, Colin L. | Dratz, Edward A. | Laws, Simon M.

Article Type: Short Communication

Abstract: After age, polymorphisms of the Apolipoprotein E (APOE ) gene are the biggest risk factor for the development of Alzheimer’s disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ɛ 2, ɛ 3, and ɛ 4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ɛ 4 (Q222K) mutation did not form dimers or complexes observed for apoE ɛ 2 & ɛ …3 proteins. Show more

Keywords: Alzheimer’s disease, APOE, biomarkers, 2D PAGE, mutation, plasma, proteogenomics

DOI: 10.3233/ADR-220075

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 165-172, 2023

Authors: Ehtezazi, Touraj | Rahman, Khalid | Davies, Rhys | Leach, Andrew G.

Article Type: Review Article

Abstract: Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-β plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has …been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17β-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments. Show more

Keywords: Alzheimer’s disease, blocking NMDA receptors, blood-brain barrier, declining cognitive function, liver dysfunction, serum bile acids

DOI: 10.3233/ADR-220071

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 173-211, 2023

Authors: Sinclair, Lindsey I. | Lawton, Michael A. | Palmer, Jennifer C. | Ballard, Clive G.

Article Type: Research Article

Abstract: Background: Depression in individuals with Alzheimer’s disease (AD) is common, distressing, difficult to treat, and inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure. Objective: We aimed to characterize depression in AD and to identify risk factors. Methods: We used data from three large dementia focused cohorts: ADNI (n  = 665 with AD, 669 normal cognition), NACC (n  = 698 with AD, 711 normal cognition), and BDR (n  = 757 with AD). Depression ratings were available using the GDS …and NPI and in addition for BDR the Cornell. A cut-off of≥8 was used for the GDS and the Cornell Scale for Depression in Dementia,≥6 for the NPI depression sub-scale, and≥2 for the NPI-Q depression sub-scale. We used logistic regression to examine potential risk factors and random effects meta-analysis and an interaction term to look for interactions between each risk factor and the presence of cognitive impairment. Results: In individual studies there was no evidence of a difference in risk factors for depressive symptoms in AD. In the meta-analysis the only risk factor which increased the risk of depressive symptoms in AD was previous depression, but information on this was only available from one study (OR 7.78 95% CI 4.03–15.03). Conclusion: Risk factors for depression in AD appear to differ to those for depression per se supporting suggestions of a different pathological process, although a past history of depression was the strongest individual risk factor. Show more

Keywords: Alzheimer’s disease, dementia, depression, depressive disorder

DOI: 10.3233/ADR-239000

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 213-225, 2023

Authors: Mendez, Mario F. | Nasir, Imaad

Article Type: Short Communication

Abstract: The differentiation of semantic variant primary progressive aphasia from dementia and Alzheimer’s disease can be difficult, particularly when the semantic anomia is pronounced. This report describes a patient who presented with complaints of memory loss and proved to have prominent semantic loss of all types of nouns, common and proper, concrete and abstract, yet continued to live independently and maintain his activities of daily living. The evaluation was consistent for semantic variant primary progressive aphasia with degradation of semantic knowledge and focal anterior temporal atrophy and hypometabolism. This report summarizes the literature and discusses the differential diagnosis of this disorder …from Alzheimer’s disease and related dementias. Show more

Keywords: Alzheimer’s disease, face recognition, semantic dementia, semantic variant primary progressive aphasia, surface dyslexia

DOI: 10.3233/ADR-230010

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 227-234, 2023

Authors: Tsamou, Maria | Kalligerou, Faidra | Ntanasi, Eva | Scarmeas, Nikolaos | Skalicky, Susanna | Hackl, Matthias | Roggen, Erwin L.

Article Type: Research Article

Abstract: Background: Late-onset or sporadic Alzheimer’s disease (sAD) is a neurodegenerative disease leading to cognitive impairment and memory loss. The underlying pathological changes take place several years prior to the appearance of the first clinical symptoms, however, the early diagnosis of sAD remains obscure. Objective: To identify changes in circulating microRNA (miR) expression in an effort to detect early biomarkers of underlying sAD pathology. Methods: A set of candidate miRs, earlier detected in biofluids from subjects at early stage of sAD, was linked to the proposed tau-driven adverse outcome pathway for memory loss. The relative expression of …the selected miRs in serum of 12 cases (mild cognitive impairment, MCI) and 27 cognitively normal subjects, recruited within the ongoing Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) study, was measured by RT-qPCR. Data on the protein levels of amyloid-β (Aβ42 ) and total/phosphorylated tau (t-tau/p-tau), in cerebrospinal fluid (CSF), and the cognitive z-scores of the participants were also retrieved. Results: Each doubling in relative expression of 13 miRs in serum changed the odds of either having MCI (versus control), or having pathological Aβ42 or pathological Aβ42 and tau (versus normal) proteins in their CSF, or was associated with the global composite z-score. Conclusion: These candidate human circulating miRs may be of great importance in early diagnosis of sAD. There is an urgent need for confirming these proposed early predictive biomarkers for sAD, contributing not only to societal but also to economic benefits. Show more

Keywords: Alzheimer’s disease, early diagnosis, microRNA, mild cognitive impairment

DOI: 10.3233/ADR-230001

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 235-248, 2023

Authors: Schmicker, Marlen | Frühling, Insa | Menze, Inga | Glanz, Wenzel | Müller, Patrick | Noesselt, Toemme | Müller, Notger G.

Article Type: Research Article

Abstract: Background: Patients with subjective cognitive decline (SCD) report memory deterioration and are at an increased risk of converting to Alzheimer’s disease (AD) although psychophysical testing does not reveal any cognitive deficit. Objective: Here, gustatory function is investigated as a potential predictor for an increased risk of progressive cognitive decline indicating higher AD risk in SCD. Methods: Measures of smell and taste perception as well as neuropsychological data were assessed in patients with subjective cognitive decline (SCD): Subgroups with an increased likelihood of the progression to preclinical AD (SCD+) and those with a lower likelihood (SCD–) were …compared to healthy controls (HC), patients with mild cognitive impairment and AD patients. The Sniffin’ Sticks test contained 12 items with different qualities and taste was measured with 32 taste stripes (sweet, salty, bitter, sour) of different concentration. Results: Only taste was able to distinguish between HC/SCD– and SCD+ patients. Conclusion: This study provides a first hint of taste as a more sensitive marker than smell for detecting preclinical AD in SCD. Longitudinal observation of cognition and pathology are necessary to further evaluate taste perception as a predictor of pathological objective decline in cognition. Show more

Keywords: Alzheimer’s disease, dementia, diagnostic marker, early diagnosis, subjective cognitive decline, taste

DOI: 10.3233/ADR220092

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 249-262, 2023

Authors: Panegyres, Peter K. | Robins, Peter

Article Type: Research Article

Abstract: Background: Controversy exists as to the role of the amyloid-β (Aβ) peptide in the pathophysiology of Alzheimer’s disease (AD). Objective: To clarify the effect of age on Aβ deposition in sporadic AD by exploring the degree of amyloid burden in patients with sporadic young onset AD (YOAD). Methods: Patients were diagnosed with YOAD with dementia starting before the age of 65 years (N = 42; males = 20, females = 22). A cross-sectional analysis of amyloid binding using positron emission tomography (PET) imaging was performed using the C-Pittsburgh Compound B (PiB). The global standardized uptake value ratios (gSUVR) were examined using the …Wilcoxon two-sample test, as were the cognitive scores between disease and healthy control populations. Differences in PiB retention in different anatomical areas were compared using the Kruskal-Wallis test. The contrast in APOE genotyping between groups was calculated with Fisher’s Exact Test. Results: Women had a median gSUVR = 2.68±0.73 and 73% had at least one APOE ɛ4 allele. Men had gSUVR = 2.37±0.54, with 80% having at least one APOE ɛ4 allele. The gSUVRs were significantly higher than the control populations for men and women and had significantly greater frequency of APOE ɛ4. Men and women analyzed together had significantly greater amyloid burden and APOE ɛ4 allele frequencies than controls, but no differences existed between them in gSUVR nor in the anatomical distribution of amyloid uptake. Conclusion: Men and women with YOAD have greater amyloid uptake than controls and have more APOE ɛ4 alleles. Our findings suggest that the Aβ peptide is operational in young onset dementia and driven by the APOE ɛ4 allele. Show more

Keywords: Alzheimer’s disease, brain amyloid, sporadic, young onset dementia

DOI: 10.3233/ADR-220110

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 263-270, 2023

Authors: Knoll, Kelly | Rhee, Yeong | Hamm, Jeremy M. | Hammer, Kimberly D.P. | Heimbuch, Halli | Holloway, Jeremy | Jurivich, Donald | Lahr, Peyton | McGrath, Brenda | Parker, Kelly | Robinson-Lane, Sheria | Stover, Emily | Tomkinson, Grant R. | McGrath, Ryan

Article Type: Research Article

Abstract: Background: Instrumental activities of daily living (IADL) are neuropsychological-driven tasks that are linked to cognitive dysfunction. Examining population-based IADL deficits may reveal insights for the presence of these impairments in the United States. Objective: This investigation sought to evaluate the prevalence and trends of IADL impairments in Americans. Methods: A secondary analysis of data from the 2006–2018 waves of the Health and Retirement Study was conducted. The overall unweighted analytic sample included 29,764 Americans aged≥50 years. Respondents indicated their ability to perform six IADLs: manage money, manage medications, use a telephone, prepare hot meals, shop for …groceries, and use a map. Persons reporting difficulty or an inability to complete an individual IADL were considered as having a task-specific impairment. Similarly, those indicating difficulty or an inability to perform any IADL were classified as having an IADL impairment. Sample weights were utilized to generate nationally-representative estimates. Results: Having an impairment in using a map (2018 wave: 15.7% (95% confidence interval (CI): 15.0–16.4) had the highest prevalence in individual IADLs regardless of wave examined. The overall prevalence of IADL impairments declined during the study period (p  < 0.001) to 25.4% (CI: 24.5–26.2) in the 2018 wave. Older Americans and women had a consistently higher prevalence of IADL impairments compared to middle-aged Americans and men, respectively. The prevalence of IADL impairments was also highest among Hispanics and non-Hispanic Blacks. Conclusion: IADL impairments have declined over time. Continued surveillance of IADLs may help inform cognitive screening, identify subpopulations at risk of impairment, and guide relevant policy. Show more

Keywords: Aging, Alzheimer’s disease, cognitive dysfunction, dementia, mass screening

DOI: 10.3233/ADR-220107

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 271-278, 2023

Authors: Fisher, Daniel W. | Tulloch, Jessica | Yu, Chang-En | Tsuang, Debby

Article Type: Research Article

Abstract: Background: Pathological amyloid-β and α -synuclein are associated with a spectrum of related dementias, ranging from Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) to Parkinson disease dementia (PDD). While these diseases share clinical and pathological features, they also have unique patterns of pathology. However, epigenetic factors that contribute to these pathological differences remain unknown. Objective: In this preliminary study, we explore differences in DNA methylation and transcription in five neuropathologically defined groups: cognitively unimpaired controls, AD, pure DLB, DLB with concomitant AD (DLBAD), and PDD. Methods: We employed an Illumina Infinium 850k array and …RNA-seq to quantify these differences in DNA methylation and transcription, respectively. We then used Weighted Gene Co-Network Expression Analysis (WGCNA) to determine transcriptional modules and correlated these with DNA methylation. Results: We found that PDD was transcriptionally unique and correlated with an unexpected hypomethylation pattern compared to the other dementias and controls. Surprisingly, differences between PDD and DLB were especially notable with 197 differentially methylated regions. WGCNA yielded numerous modules associated with controls and the four dementias: one module was associated with transcriptional differences between controls and all the dementias as well as having significant overlap with differentially methylated probes. Functional enrichment demonstrated that this module was associated with responses to oxidative stress. Conclusion: Future work that extends these joint DNA methylation and transcription analyses will be critical to better understanding of differences that contribute to varying clinical presentation across dementias. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE, dementia, DNA methylation, Lewy bodies, Lewy body disease, Parkinson’s disease, RNA-seq, transcriptome

DOI: 10.3233/ADR220114

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 279-297, 2023

Authors: O’Caoimh, Rónán | Molloy, D. William

Article Type: Research Article

Abstract: Background: Short cognitive screening instruments (CSI) are required to identify cognitive impairment in busy outpatient clinics. While the Six Item Cognitive Impairment Test (6CIT) is commonly used, its accuracy in those with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) and against more widely-used CSIs is less well established. Objective: To examine the diagnostic accuracy of the 6CIT against the Montreal Cognitive Assessment (MoCA) and Quick Mild Cognitive Impairment (Qmci ) screen across the cognitive spectrum in a memory clinic population. Methods: In total, 142 paired assessments were available (21 with SCD, 32 MCI, and …89 with dementia). Consecutive patients underwent a comprehensive assessment and were screened using the 6CIT, Qmci , and MoCA. Accuracy was determined from the area under receiver operating characteristic curves (AUC). Results: The median age of patients was 76 (±11) years; 68% were female. The median 6CIT score was 10/28 (±14). The 6CIT was strongly, negatively, and statistically significantly correlated with the Qmc i (r  = –0.84) and MoCA (r  = –0.86). The 6CIT had good accuracy for separating cognitive impairment (MCI or dementia) from SCD, (AUC:0.88; 0.82–0.94), similar to the MoCA (AUC:0.92; 0.87–0.97, p  = 0.308), but statistically lower than the Qmci (AUC:0.96; 0.94–0.99, p  = 0.01). The 6CIT was faster to administer, median time 2.05 minutes versus 4.38 and 9.5 for the Qmci and MoCA, respectively. Conclusion: While the Qmci was more accurate than the 6CIT, the shorter administration time of the 6CIT, suggests it may be useful when assessing or monitoring cognitive impairment in busy memory clinics, though larger samples are required to evaluate. Show more

Keywords: Cognitive screening, diagnostic accuracy, memory clinic, Six Item Cognitive Impairment Test, Montreal Cognitive Assessment, Quick Mild Cognitive Impairment screen

DOI: 10.3233/ADR220117

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 299-306, 2023

Authors: Nakanishi, Miharu | Ogawa, Asao | Sakai, Mai | Yoshii, Hatsumi | Miyashita, Mitsuhiro | Yamasaki, Syudo | Nishida, Atsushi

Article Type: Short Communication

Abstract: This study examined the longitudinal association between dementia, activity participation, the coronavirus disease 2019 pandemic period, and 1-year mental health changes. We obtained data from the National Health and Aging Trends Study in the United States. We included 4,548 older adult participants of two or more survey rounds between 2018 and 2021. We identified baseline dementia status, and assessed depressive symptoms and anxiety at baseline and follow-up. Dementia and poor activity participation were independently associated with an increased prevalence of depressive symptoms and anxiety. Dementia care and support should address emotional and social needs under continued public health restrictions.

Keywords: Activity participation, Alzheimer’s disease, anxiety, COVID-19, dementia, depression

DOI: 10.3233/ADR-230019

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 307-315, 2023

Authors: Morrison-Koechl, Jill | Fearon, Danielle O. | Fernandes, Myra A. | Tyas, Suzanne L.

Article Type: Research Article

Abstract: Background: Risk factors for dementia, such as Alzheimer’s disease, are complex and span a lifetime. Exploring novel factors, such as characteristics of writing, may provide insight into dementia risk. Objective: To investigate the association between emotional expressivity and risk of dementia in the context of a previously identified risk factor, written language skills. Methods: The Nun Study recruited 678 religious sisters aged 75 + years. Of these, 149 U.S.-born participants had archived autobiographies handwritten at a mean age of 22 years. The autobiographies were scored for frequency of emotion word usage and language skills (e.g., idea density). The …association of emotional expressivity and a four-level composite variable (combining high/low emotional expressivity and high/low idea density) with dementia was assessed using logistic regression models adjusted for age, education, and apolipoprotein E. Results: Within the composite variable, odds of dementia increased incrementally, with opposing effects of emotional expressivity across the two idea density levels. Compared to the referent category (low emotional expressivity/high idea density), the risk of dementia increased in those with high emotional expressivity/high idea density (OR = 2.73, 95% CI = 1.05–7.08), while those with low emotional expressivity/low idea density had the highest risk (OR = 18.58, 95% CI = 4.01–86.09). Conclusion: Dementia risk is better captured by inclusion of multiple measures relating to characteristics of writing. Emotional expressivity may be protective when individuals are at increased risk due to poor written language skills (i.e., low idea density), but detrimental when not at risk (i.e., high idea density). Our findings indicate that emotional expressivity is a contextually-dependent novel risk factor for dementia. Show more

Keywords: Alzheimer’s disease, cognition, dementia, emotions, language, life course perspective, logistic models, longitudinal studies, risk factors

DOI: 10.3233/ADR-220106

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 317-326, 2023

Authors: Schramm, Sara | Krizanovic, Nela | Roggenbuck, Ulla | Jöckel, Karl-Heinz | Herring, Arne | Keyvani, Kathy | Jokisch, Martha

Article Type: Research Article

Abstract: Background: Blood kallikrein-8 is supposed to be a biomarker for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD), a precursor of AD dementia. Little is known about the association of kallikrein-8 and non-AD type dementias. Objective: To investigate whether blood kallikrein-8 is elevated in individuals with non-amnestic MCI (naMCI), which has a higher probability to progress to a non-AD type dementia, compared with cognitively unimpaired (CU) controls. Methods: We measured blood kallikrein-8 at ten-year follow-up (T2) in 75 cases and 75 controls matched for age and sex who were participants of the population-based Heinz Nixdorf …Recall study (baseline: 2000–2003). Cognitive performance was assessed in a standardized manner at five (T1) and ten-year follow-up. Cases were CU or had subjective cognitive decline (SCD) at T1 and had naMCI at T2. Controls were CU at both follow-ups. The association between kallikrein-8 (per 500 pg/ml increase) and naMCI was estimated using conditional logistic regression: odds ratios (OR) and 95% confidence intervals (95% CI) were determined, adjusted for inter-assay variability and freezing duration. Results: Valid kallikrein-8 values were measured in 121 participants (45% cases, 54.5% women, 70.5±7.1 years). In cases, the mean kallikrein-8 was higher than in controls (922±797 pg/ml versus 884±782 pg/ml). Kallikrein-8 was not associated with having naMCI compared to being CU (adjusted; OR: 1.03 [95% CI: 0.80–1.32]). Conclusion: This is the first population-based study that shows that blood kallikrein-8 tends not to be elevated in individuals with naMCI compared with CU. This adds to the evidence of the possible AD specificity of kallikrein-8. Show more

Keywords: Alzheimer’s disease, biomarker, dementia, Heinz Nixdorf Recall study, kallikrein-8, mild cognitive impairment, neurodegeneration, neuropsin

DOI: 10.3233/ADR-220073

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 327-337, 2023

Authors: den Hoedt, Sandra | Dorst-Lagerwerf, Kristien Y. | de Vries, Helga E. | Rozemuller, Annemieke J.M. | Scheltens, Philip | Walter, Jochen | Sijbrands, Eric J.G. | Martinez-Martinez, Pilar | Verhoeven, Adrie J.M. | Teunissen, Charlotte E. | Mulder, Monique T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD. Objective: To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD. Methods: Patients homozygous for APOE4 and non-APOE4 carriers with mild cognitive impairment (MCI; n  = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n  = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ42 levels …in CSF were determined by immunoassay. Results: APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p  = 0.042), SM(d18:1/18:0) (p  = 0.026), and Aβ42 (p  < 0.001) in CSF than non-APOE4 carriers. CSF-Aβ42 correlated with Cer(d18:1/18:0), SM(d18:1/18:0), and SM(d18:1/18:1) levels in APOE4 homozygotes (r  > 0.49; p  < 0.032) and with Cer(d18:1/24:1) in non-APOE4 carriers (r  = 0.50; p  = 0.025). CSF-Aβ42 correlated positively with Cer(d18:1/24:0) in MCI (p  = 0.028), but negatively in SCD patients (p  = 0.019). Levels of Cer(d18:1/22:0) and long-chain SMs were inversely correlated with Mini-Mental State Examination score among MCI patients, independent of APOE4 genotype (r < –0.47; p  < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the APOE genotype or the cognitive state. In HDL, ratios of Cer(d18:1/18:0) and Cer(d18:1/22:0) to cholesterol were higher in APOE4 homozygotes than in non-APOE4 carriers (p  = 0.048 and 0.047, respectively). Conclusion: The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, Apolipoprotein E4, ceramides, cerebrospinal fluid, cognitive dysfunction, lipoproteins, sphingolipids

DOI: 10.3233/ADR220072

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 339-354, 2023

Authors: Pais, Marcos V. | Forlenza, Orestes V. | Diniz, Breno S.

Article Type: Review Article

Abstract: Recently, low-sensitive plasma assays have been replaced by new ultra-sensitive assays such as single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) with higher accuracy in the determination of plasma biomarkers of Alzheimer’s disease (AD). Despite the significant variability, many studies have established in-house cut-off values for the most promising available biomarkers. We first reviewed the most used laboratory methods and assays to measure plasma AD biomarkers. Next, we review studies focused on the diagnostic performance of these biomarkers to identify AD cases, predict cognitive decline in pre-clinical AD cases, and differentiate AD cases …from other dementia. We summarized data from studies published until January 2023. A combination of plasma Aβ42/40 ratio, age, and APOE status showed the best accuracy in diagnosing brain amyloidosis with a liquid chromatography–mass spectrometry (LC–MS) assay. Plasma p-tau217 has shown the best accuracy in distinguishing Aβ-PET+ from Aβ-PET–even in cognitively unimpaired individuals. We also summarized the different cut-off values for each biomarker when available. Recently developed assays for plasma biomarkers have undeniable importance in AD research, with improved analytical and diagnostic performance. Some biomarkers have been extensively used in clinical trials and are now clinically available. Nonetheless, several challenges remain to their widespread use in clinical practice. Show more

Keywords: Alzheimer’s disease, amyloid-β , GFAP, NfL protein, plasma biomarkers, phosphorylated tau

DOI: 10.3233/ADR-230029

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 355-380, 2023

Authors: Das, Tushar Kanti | Ganesh, Bhanu Priya | Fatima-Shad, Kaneez

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and stroke are two interrelated neurodegenerative disorders which are the leading cause of death and affect the neurons in the brain and central nervous system. Although amyloid-β aggregation, tau hyperphosphorylation, and inflammation are the hallmarks of AD, the exact cause and origin of AD are still undefined. Recent enormous fundamental discoveries suggest that the amyloid hypothesis of AD has not been proven and anti-amyloid therapies that remove amyloid deposition have not yet slowed cognitive decline. However, stroke, mainly ischemic stroke (IS), is caused by an interruption in the cerebral blood flow. Significant features of both disorders are …the disruption of neuronal circuitry at different levels of cellular signaling, leading to the death of neurons and glial cells in the brain. Therefore, it is necessary to find out the common molecular mechanisms of these two diseases to understand their etiological connections. Here, we summarized the most common signaling cascades including autotoxicity, ApoE4, insulin signaling, inflammation, mTOR-autophagy, notch signaling, and microbiota-gut-brain axis, present in both AD and IS. These targeted signaling pathways reveal a better understanding of AD and IS and could provide a distinguished platform to develop improved therapeutics for these diseases. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, excitotoxicity, glucose, insulin, ischemic stroke, microbiota-gut-brain axis, mTOR-autophagy, Notch signaling, PI3K/Akt

DOI: 10.3233/ADR-220108

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 381-398, 2023

Authors: Won, Junyeon | Nielson, Kristy A. | Smith, J. Carson

Article Type: Research Article

Abstract: Background: Despite growing evidence regarding the association between exercise training (ET) and functional brain network connectivity, little is known about the effects of ET on large-scale within- and between-network functional connectivity (FC) of core brain networks. Objective: We investigated the effects of ET on within- and between-network functional connectivity of the default mode network (DMN), frontoparietal network (FPN), and salience network (SAL) in older adults with intact cognition (CN) and older adults diagnosed with mild cognitive impairment (MCI). The association between ET-induced changes in FC and cognitive performance was examined. Methods: 33 older adults (78.0±7.0 years; …16 MCI and 17 CN) participated in this study. Before and after a 12-week walking ET intervention, participants underwent a graded exercise test, Controlled Oral Word Association Test (COWAT), Rey Auditory Verbal Learning Test (RAVLT), a narrative memory test (logical memory; LM), and a resting-state fMRI scan. We examined the within (W ) and between (B ) network connectivity of the DMN, FPN, and SAL. We used linear regression to examine associations between ET-related changes in network connectivity and cognitive function. Results: There were significant improvements in cardiorespiratory fitness, COWAT, RAVLT, and LM after ET across participants. Significant increases in DMNW and SALW , and DMN-FPNB , DMN-SALB , and FPN-SALB were observed after ET. Greater SALW and FPN-SALB were associated with enhanced LM immediate recall performance after ET in both groups. Conclusion: Increased within- and between-network connectivity following ET may subserve improvements in memory performance in older individuals with intact cognition and with MCI due to Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive function, exercise training, functional connectivity, mild cognitive impairment, neural network, older adults, physical activity

DOI: 10.3233/ADR-220062

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 399-413, 2023

Authors: Benichou Haziot, Carla | Birak, Kulbir Singh

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease, yet it currently lacks effective treatment due to its complex etiology. The pathological changes in AD have been linked to the neurotoxic immune responses following aggregation of Aβ and phosphorylated tau. The gut microbiota (GM) is increasingly studied for modulating neuroinflammation in neurodegenerative diseases and in vivo studies emerge for AD. This critical review selected 7 empirical preclinical studies from 2019 onwards assessing therapy approaches targeting GM modulating microglia neuroinflammation in AD mouse models. Results from probiotics, fecal microbiota transplantation, and drugs were compared and contrasted, including for cognition, neuroinflammation, …and toxic aggregation of proteins. Studies consistently reported significant amelioration or prevention of cognitive deficits, decrease in microglial activation, and lower levels of pro-inflammatory cytokines, compared to AD mouse models. However, there were differences across papers for the brain regions affected, and changes in astrocytes were inconsistent. Aβ plaques deposition significantly decreased in all papers, apart from Byur dMar Nyer lNga Ril Bu (BdNlRB ) treatment. Tau phosphorylation significantly declined in 5 studies. Effects in microbial diversity following treatment varied across studies. Findings are encouraging regarding the efficacy of study but information on the effect size is limited. Potentially, GM reverses GM derived abnormalities, decreasing neuroinflammation, which reduces AD toxic aggregations of proteins in the brain, resulting in cognitive improvements. Results support the hypothesis of AD being a multifactorial disease and the potential synergies through multi-target approaches. The use of AD mice models limits conclusions around effectiveness, as human translation is challenging. Show more

Keywords: Alzheimer’s disease, brain-gut axis, dysbiosis, fecal microbiota transplantation, microglia, neurodegenerative diseases, probiotics, therapeutics

DOI: 10.3233/ADR-220097

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 415-431, 2023

Authors: Silva, Rosa | Bobrowicz-Campos, Elzbieta | Santos-Costa, Paulo | Cardoso, Remy | Bernardo, Joana | Santana, Elaine | Almeida, Inês | Loureiro, Ricardo | Cardoso, Daniela | Apóstolo, João

Article Type: Systematic Review

Abstract: Background: In a society increasingly committed to promoting an active life in the community, new resources are needed to respond to the needs of citizens with Alzheimer’s disease and other forms of dementia. The potential of several individual cognitive interventions to be provided by caregivers has been explored in the literature. Objective: To synthesize the best available evidence on the effectiveness of caregiver-provided individual cognitive interventions in older adults with dementia. Methods: Systematic review of experimental studies on individual cognitive interventions for older adults with dementia. An initial search of MEDLINE and CINAHL was undertaken. Another …search for published and unpublished studies was performed on major healthcare-related online databases in March 2018 and updated in August 2022. This review considered studies that included older adults with dementia, aged 60 years and over. All studies that met the inclusion criteria were assessed for methodological quality using a JBI standardized critical appraisal checklist. Data were extracted using a JBI data extraction form for experimental studies. Results: Eleven studies were included: eight randomized controlled trials and three quasi-experimental studies. Caregiver-provided individual cognitive interventions had several beneficial effects in cognitive domains, including memory, verbal fluency, attention, problem-solving, and autonomy in activities of daily living. Conclusion: These interventions were associated with moderate improvements in cognitive performance and benefits in activities of daily living. The findings highlight the potential of caregiver-provided individual cognitive interventions for older adults with dementia. Show more

Keywords: Alzheimer’s disease, caregivers, cognitive therapies, dementia, major neurocognitive disorder, older adults, systematic review

DOI: 10.3233/ADR-220115

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 433-459, 2023

Authors: Eaton, Jacqueline | Neller, Sarah | Fernandez Cajavilca, Moroni | Johnson, Julene K. | Ellington, Lee

Article Type: Short Communication

Abstract: Interventions that actively engage dementia caregivers show promise in reducing the negative outcomes of caregiving but lack optimization and systematic testing. The purpose of this manuscript is to describe an iterative process developed to refine an intervention to enhance active engagement. A three-stage review process with content experts was developed to refine activities in preparation for focus group feedback and pilot testing. We identified caregiving vignettes, reorganized engagement techniques, and optimized focus group activities for online delivery to promote caregiver access and safety. The framework developed from this process is included, along with a template to guide intervention refinement.

Keywords: Alzheimer’s disease, caregivers, dementia, intervention study, trial protocol

DOI: 10.3233/ADR-220096

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 461-467, 2023

Authors: Roveta, Fausto | Marcinnò, Andrea | Grassini, Alberto | Ferrandes, Fabio | Cermelli, Aurora | Boschi, Silvia | Gallone, Salvatore | Atzori, Cristiana | Imperiale, Daniele | Dentelli, Patrizia | Pasini, Barbara | Brusco, Alfredo | Rubino, Elisa | Rainero, Innocenzo

Article Type: Short Communication

Abstract: We describe a 52-year-old patient with a progressive visuospatial disorder and apraxia. Neuropsychological assessment, neuroradiological findings, and Alzheimer’s disease (AD) core biomarker assay on cerebrospinal fluid led to a diagnosis of posterior cortical atrophy due to AD. We performed a next generation sequencing dementia-gene panel and found the c.1301 C>T p.(Ala434Val) variant in the Presenilin1 (PSEN1) gene. The missense change affects the PAL (Pro433-Ala434-Leu435) motif critical for catalytic activity of the macromolecular γ -secretase complex. Evolutionary and integrated bioinformatic tools predicted a deleterious effect of the variant supporting its role in the AD pathogenesis.

Keywords: Alzheimer’s disease, case reports, genetics, posterior cortical atrophy

DOI: 10.3233/ADR230023

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 469-473, 2023

Authors: Milicic, Lidija | Porter, Tenielle | Vacher, Michael | Laws, Simon M.

Article Type: Review Article

Abstract: Epigenetic mechanisms such as DNA methylation have been implicated in a number of diseases including cancer, heart disease, autoimmune disorders, and neurodegenerative diseases. While it is recognized that DNA methylation is tissue-specific, a limitation for many studies is the ability to sample the tissue of interest, which is why there is a need for a proxy tissue such as blood, that is reflective of the methylation state of the target tissue. In the last decade, DNA methylation has been utilized in the design of epigenetic clocks, which aim to predict an individual’s biological age based on an algorithmically defined set …of CpGs. A number of studies have found associations between disease and/or disease risk with increased biological age, adding weight to the theory of increased biological age being linked with disease processes. Hence, this review takes a closer look at the utility of DNA methylation as a biomarker in aging and disease, with a particular focus on Alzheimer’s disease. Show more

Keywords: Aging, Alzheimer’s disease, dementia, DNA methylation, epigenetics

DOI: 10.3233/ADR-220109

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 475-503, 2023

Authors: Ávila-Villanueva, Marina | Dolado, Alberto Marcos | Fernández-Blázquez, Miguel

Article Type: Review Article

Abstract: The development of Alzheimer’s disease (AD) follows three consecutive phases: namely preclinical, prodromal or mild cognitive impairment (MCI), and dementia. In addition, the preclinical phase can be divided into subphases related to the presence of biomarkers that appear at different points before the onset of MCI. Indeed, an early risk factor could promote the appearance of additional ones through a continuum. The presence of various risk factors may trigger specific biomarkers. In this review, we comment on how modifiable risk factors for AD may be reverted, thus correlating with a possible decrease in the specific biomarkers for the disease. Finally, …we discuss the development of a suitable AD prevention strategy by targeting modifiable risk factors, thereby increasing the level of “precision medicine” in healthcare systems worldwide. Show more

Keywords: Alzheimer’s disease continuum, modifiable risk factors, precision medicine, sleep disturbances

DOI: 10.3233/ADR220100

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 505-512, 2023

Authors: Torrealba, Eduardo | Aguilar-Zerpa, Norka | Garcia-Morales, Pilar | Díaz, Mario

Article Type: Review Article

Abstract: Despite advances in the detection of biomarkers and in the design of drugs that can slow the progression of Alzheimer’s disease (AD), the underlying primary mechanisms have not been elucidated. The diagnosis of AD has notably improved with the development of neuroimaging techniques and cerebrospinal fluid biomarkers which have provided new information not available in the past. Although the diagnosis has advanced, there is a consensus among experts that, when making the diagnosis in a specific patient, many years have probably passed since the onset of the underlying processes, and it is very likely that the biomarkers in use and …their cutoffs do not reflect the true critical points for establishing the precise stage of the ongoing disease. In this context, frequent disparities between current biomarkers and cognitive and functional performance in clinical practice constitute a major drawback in translational neurology. To our knowledge, the In-Out-test is the only neuropsychological test developed with the idea that compensatory brain mechanisms exist in the early stages of AD, and whose positive effects on conventional tests performance can be reduced in assessing episodic memory in the context of a dual-task, through which the executive auxiliary networks are ‘distracted’, thus uncover the real memory deficit. Furthermore, as additional traits, age and formal education have no impact on the performance of the In-Out-test . Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, early detection, hippocampal amnesia paradigm tests, mild cognitive impairment, prodromal Alzheimer’s disease, subjective memory complaints

DOI: 10.3233/ADR-220116

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 513-525, 2023

Authors: Bhattacharyya, Sumit | Tobacman, Joanne K.

Article Type: Research Article

Abstract: Background: Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer’s disease (AD), and the impact of modified chondroitin sulfates is being investigated in several animal and cell-based models of AD. Published reports have shown the role of accumulation of chondroitin 4-sulfate and decline in Arylsulfatase B (ARSB; B-acetylgalactosamine-4-sulfatase) in other pathology, including nerve injury, traumatic brain injury, and spinal cord injury. However, the impact of ARSB deficiency on AD pathobiology has not been reported, although changes in ARSB were associated with AD in two prior reports. The enzyme ARSB removes 4-sulfate groups from the non-reducing end of chondroitin …4-sulfate and dermatan sulfate and is required for their degradation. When ARSB activity declines, these sulfated glycosaminoglycans accumulate, as in the inherited disorder Mucopolysaccharidosis VI. Objective: Reports about chondroitin sulfate, chondroitin sulfate proteoglycans, and chondroitin sulfatases in AD were reviewed. Methods: Measurements of SAA2, iNOS, lipid peroxidation, chondroitin sulfate proteoglycan 4 (CSPG4), and other parameters were performed in cortex and hippocampus from ARSB-null mice and controls by QRT-PCR, ELISA, and other standard assays. Results: SAA2 mRNA expression and protein, CSPG4 mRNA, chondroitin 4-sulfate, and iNOS were increased significantly in ARSB-null mice. Measures of lipid peroxidation and redox state were significantly modified. Conclusion: Findings indicate that decline in ARSB leads to changes in expression of parameters associated with AD in the hippocampus and cortex of the ARSB-deficient mouse. Further investigation of the impact of decline in ARSB on the development of AD may provide a new approach to prevent and treat AD. Show more

Keywords: Alzheimer’s disease, arylsulfatase B, chondroitin sulfate, glycosaminoglycan, iNOS, lipid peroxidation, N-acetylgalactosamine-4-sulfatase, SAA, thiol

DOI: 10.3233/ADR-230028

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 527-534, 2023

Authors: Musaeus, Christian Sandøe | Gleerup, Helena Sophia | Hasselbalch, Steen Gregers | Waldemar, Gunhild | Simonsen, Anja Hviid

Article Type: Research Article

Abstract: Background: Studies have found a disruption of the blood-brain barrier (BBB) in patients with Alzheimer’s disease (AD), but there is little evidence of the changes in the BBB over time. The cerebrospinal fluid’s (CSF) protein concentration can be used as an indirect measurement for the permeability of the BBB using the CSF/plasma albumin quotient (Q-Alb) or total CSF protein. Objective: In the current study, we wanted to investigate the changes in Q-Alb in patients with AD over time. Methods: A total of 16 patients diagnosed with AD, who had at least two lumbar punctures performed, were …included in the current study. Results: The difference in Q-Alb over time did not show a significant change. However, Q-Alb increased over time if the time interval was > 1 year between the measurements. No significant associations between Q-Alb and age, Mini-Mental State Examination, or AD biomarkers were found. Conclusion: The increase in Q-Alb suggests that there is an increased leakage through the BBB, which may become more prominent as the disease progresses. This may be a sign of progressive underlying vascular pathology, even in patients with AD without major vascular lesions. More studies are needed to further understand the role of BBB integrity in patients with AD over time and the association with the progression of the disease. Show more

Keywords: Albumin, Alzheimer’s disease, blood-brain barrier, cerebrospinal fluid, CSF/plasma albumin quotient, Q-Alb

DOI: 10.3233/ADR-230016

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 535-541, 2023

Authors: Thompson, Fintan | Russell, Sarah | Quigley, Rachel | Sagigi, Betty | Miller, Gavin | Esterman, Adrian | Harriss, Linton R. | Taylor, Sean | McDermott, Robyn | Strivens, Edward

Article Type: Research Article

Abstract: Background: Reducing the burden of dementia in First Nations populations may be addressed through developing population specific methods to quantify future risk of dementia. Objective: To adapt existing dementia risk models to cross-sectional dementia prevalence data from a First Nations population in the Torres Strait region of Australia in preparation for follow-up of participants. To explore the diagnostic utility of these dementia risk models at detecting dementia. Methods: A literature review to identify existing externally validated dementia risk models. Adapting these models to cross-sectional data and assessing their diagnostic utility through area under the receiver operating …characteristic curve (AUROC) analyses and calibration using Hosmer-Lemeshow Chi2 . Results: Seven risk models could be adapted to the study data. The Aging, Cognition and Dementia (AgeCoDe) study, the Framingham Heart Study (FHS), and the Brief Dementia Screening Indicator (BDSI) had moderate diagnostic utility in identifying dementia (i.e., AUROC >0.70) before and after points for older age were removed. Conclusion: Seven existing dementia risk models could be adapted to this First Nations population, and three had some cross-sectional diagnostic utility. These models were designed to predict dementia incidence, so their applicability to identify prevalent cases would be limited. The risk scores derived in this study may have prognostic utility as participants are followed up over time. In the interim, this study highlights considerations when transporting and developing dementia risk models for First Nations populations. Show more

Keywords: Alzheimer’s disease, Australia, dementia, diagnostic, First Nations, Indigenous, risk models

DOI: 10.3233/ADR-220093

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 543-555, 2023

Authors: Sehar, Ujala | Rawat, Priyanka | Choudhury, Moumita | Boles, Annette | Culberson, John | Khan, Hafiz | Malhotra, Keya | Basu, Tanisha | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and Alzheimer’s disease-related disorders (ADRD) are late-onset, age-related progressive neurodegenerative disorders, characterized by memory loss and multiple cognitive impairments. Current research indicates that Hispanic Americans are at an increased risk for AD/ADRD and other chronic conditions such as diabetes, obesity, hypertension, and kidney disease, and given their rapid growth in numbers, this may contribute to a greater incidence of these disorders. This is particularly true for the state of Texas, where Hispanics are the largest group of ethnic minorities. Currently, AD/ADRD patients are taken care by family caregivers, which puts a tremendous burden on family caregivers who …are usually older themselves. The management of disease and providing necessary/timely support for patients with AD/ADRD is a challenging task. Family caregivers support these individuals in completing basic physical needs, maintaining a safe living environment, and providing necessary planning for healthcare needs and end-of-life decisions for the remainder of the patient’s lifetime. Family caregivers are mostly over 50 years of age and provide all-day care for individuals with AD/ADRD, while also managing their health. This takes a significant toll on the caregiver’s own physiological, mental, behavioral, and social health, in addition to low economic status. The purpose of our article is to assess the status of Hispanic caregivers. We also focused on effective interventions for family caregivers of persons with AD/ADRD involving both educational and psychotherapeutic components, and a group format further enhances effectiveness. Our article discusses innovative methods and validations to support Hispanic family caregivers in rural West Texas. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease-related disorders, diabetes, family caregivers, Hispanics, obesity, psychotherapeutic components

DOI: 10.3233/ADR-220094

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 557-574, 2023

Authors: Wang, Hui Jue | Kusumo, Raphael W. | Kiss, Alex | Tennen, Gayla | Marotta, Giovanni | Viaje, Shirley | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Agitation is a disabling neuropsychiatric symptom of dementia. Pro re nata (PRN) injections of psychotropics can be administered for severe acute agitation, but little is known about the frequency of their actual use. Objective: Characterize actual use of injectable PRN psychotropics for severe acute agitation in Canadian long-term care (LTC) residents with dementia and compare use before and during the COVID-19 pandemic. Methods: Residents from two Canadian LTC facilities with orders for PRN haloperidol, olanzapine, or lorazepam between January 1, 2018– May 1, 2019 (i.e., pre-COVID-19) and January 1, 2020– May 1, 2021 (i.e., COVID-19) …were identified. Electronic medical records were reviewed to document PRN injections of psychotropic medications and collect data on reason and demographic characteristics. Descriptive statistics were used to characterize frequency, dose, and indications of use, and multivariate regression models were used to compare use between time periods. Results: Of the 250 residents, 45 of 103 (44%) people in the pre-COVID-19 period and 85 of 147 (58%) people in the COVID-19 period with standing orders for PRN psychotropics received ≥1 injections. Haloperidol was the most frequently used agent in both time periods (74% (155/209 injections) pre-COVID-19; 81% (323/398 injections) during COVID-19). Residents in the COVID-19 period were almost two times more likely to receive injections compared with those in the pre-COVID-19 period (odds ratio = 1.96; 95% CI = 1.15–3.34; p  = 0.01). Conclusion: Our results suggest that use of PRN injections increased in LTC during the pandemic and contribute to the mounting evidence that agitation worsened during that time. Show more

Keywords: Alzheimer’s disease, antipsychotic agents, behavioral symptoms, benzodiazepines, COVID-19, dementia, haloperidol, lorazepam, olanzapine, psychotropic drugs

DOI: 10.3233/ADR-230009

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 575-587, 2023

Authors: Ash, Sharon | Nevler, Naomi | Irwin, David J. | Shellikeri, Sanjana | Rascovsky, Katya | Shaw, Leslie | Lee, Edward B. | Trojanowski, John Q. | Grossman, Murray

Article Type: Research Article

Abstract: Background: Apraxia of speech (AOS) is a core feature of nonfluent/agrammatic primary progressive aphasia (naPPA), but its precise characteristics and the prevalence of AOS features in spontaneous speech are debated. Objective: To assess the frequency of features of AOS in the spontaneous, connected speech of individuals with naPPA and to evaluate whether these features are associated with an underlying motor disorder such as corticobasal syndrome or progressive supranuclear palsy. Methods: We examined features of AOS in 30 patients with naPPA using a picture description task. We compared these patients to 22 individuals with behavioral variant frontotemporal …dementia and 30 healthy controls. Each speech sample was evaluated perceptually for lengthened speech segments and quantitatively for speech sound distortions, pauses between and within words, and articulatory groping. We compared subgroups of naPPA with and without at least two features of AOS to assess the possible contribution of a motor impairment to speech production deficits. Results: naPPA patients produced both speech sound distortions and other speech sound errors. Speech segmentation was found in 27/30 (90%) of individuals. Distortions were identified in 8/30 (27%) of individuals, and other speech sound errors occurred in 18/30 (60%) of individuals. Frequent articulatory groping was observed in 6/30 (20%) of individuals. Lengthened segments were observed rarely. There were no differences in the frequencies of AOS features among naPPA subgroups as a function of extrapyramidal disease. Conclusion: Features of AOS occur with varying frequency in the spontaneous speech of individuals with naPPA, independently of an underlying motor disorder. Show more

Keywords: Language, phonetics, primary progressive nonfluent aphasia, speech, verbal apraxia

DOI: 10.3233/ADR-220089

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 589-604, 2023

Authors: Bussè, Cinzia | Zorzi, Giovanni | Pettenuzzo, Ilaria | Mozzetta, Stefano | Cagnin, Annachiara

Article Type: Short Communication

Abstract: Behavioral frontotemporal dementia (bvFTD) may present with episodic memory deficits. In 38 patients with bvFTD and 61 with Alzheimer’s disease (AD) specific measures of verbal memory (learning curves and serial position effects) were studied through the Rey Auditory Verbal Learning test. Forty-two percent of bvFTD showed deficits of delayed recall memory similar to that found in AD including the serial position effects. Amnestic bvFTD had more severe atrophy in the left mesial temporal lobe than non-amnestic bvFTD. AD-like memory deficits are not infrequent in bvFTD and may be in part related to mesial temporal lobe atrophy.

Keywords: Alzheimer’s disease, dementia, frontotemporal dementia, learning, memory

DOI: 10.3233/ADR-230015

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 605-612, 2023

Authors: Ratis, Renan C. | Dacoregio, Maria I. | Simão-Silva, Daiane P. | Mateus, Rogério P. | Machado, Luciana P.B. | Bonini, Juliana S. | Silva, Weber Claudio Francisco Nunes da

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) has several risk factors. APOE4 is the main one, and it has been suggested that there may be a synergy between it and BCHE-K as a risk factor. Objective: To investigate the association between APOE4 and BCHE-K as a risk factor for AD. Methods: We searched PubMed, Web of Science, Embase, and Scopus on August 8, 2021 for studies that analyzed the association of APOE4 and BCHE-K with AD. The random effect model was performed in meta-analysis according to age group. A chi-square was performed with …the meta-analysis data to verify if the effect found is not associated only with the E4 allele. Results: Twenty-one studies with 6,853 subjects (3,528 AD and 3,325 Controls) were included in the meta-analysis. The quality of the evidence is moderate. There is a positive E4-K association for subjects with AD as shown by the odds ratio of 3.43. The chi-square meta test, which measures the probability that the E4-K association is due to chance, has an odds ratio of 6.155, indicating that the E4-K association is not a random event. The odds ratio of an E4-K association in subjects with AD increases to OR 4.46 for the 65- to 75-year-old group and OR 4.15 for subjects older than 75 years. The probability that the E4-K association is due to chance is ruled out by chi-square meta test values of OR 8.638 and OR 9.558. Conclusion: The synergy between APOE4 and BCHE-K is a risk factor for late-onset AD. Show more

Keywords: Alzheimer’s disease, APOE, BaβAC, cholinesterase, dementia, genetics, odds ratio

DOI: 10.3233/ADR-220084

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 613-625, 2023

Authors: Oh, Jean | Crockett, Rachel A. | Hsu, Chun-Liang | Dao, Elizabeth | Tam, Roger | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: As the aging population grows, there is an increasing need to develop accessible interventions against risk factors for cognitive impairment and dementia, such as cerebral small vessel disease (CSVD). The progression of white matter hyperintensities (WMHs), a key hallmark of CSVD, can be slowed by resistance training (RT). We hypothesize RT preserves white matter integrity and that this preservation is associated with improved cognitive and physical function. Objective: To determine if RT preserves regional white matter integrity and if any changes are associated with cognitive and physical outcomes. Methods: Using magnetic resonance imaging data from …a 12-month randomized controlled trial, we compared the effects of a twice-weekly 60-minute RT intervention versus active control on T1-weighted over T2-weighted ratio (T1w/T2w; a non-invasive proxy measure of white matter integrity) in a subset of study participants (N = 21 females, mean age = 69.7 years). We also examined the association between changes in T1w/T2w with two key outcomes of the parent study: (1) selective attention and conflict resolution, and (2) peak muscle power. Results: Compared with an active control group, RT increased T1w/T2w in the external capsule (p  = 0.024) and posterior thalamic radiations (p  = 0.013) to a greater degree. Increased T1w/T2w in the external capsule was associated with an increase in peak muscle power (p  = 0.043) in the RT group. Conclusion: By maintaining white matter integrity, RT may be a promising intervention to counteract the pathological changes that accompany CSVD, while improving functional outcomes such as muscle power. Show more

Keywords: Aged, Alzheimer’s disease, cerebral small vessel diseases, dementia, magnetic resonance imaging, randomized controlled trial, resistance training, white matter

DOI: 10.3233/ADR-220113

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 627-639, 2023

Authors: Cahan, Joshua G. | Vassar, Robert | Bonakdarpour, Borna

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of amyloid-β42 (Aβ42 ) and phosphorylated-tau help clinicians accurately diagnose Alzheimer’s disease (AD). Whether biomarkers help prognosticate behavioral and psychological symptoms of dementia (BPSD) is unclear. Objective: Determine whether CSF biomarker levels aid prognostication of BPSD in AD. Methods: This retrospective cohort study included patients over 65 with a diagnosis of AD based on CSF biomarkers. We measured time from CSF testing to the first antipsychotic use in the following months. We then analyzed time to antipsychotic (AP) use with respect to Aβ42 , total tau, phosphorylated tau, and amyloid-to-tau …index using a survival analysis approach. Results: Of 86 AD patients (average 72±5 years, 46.5% male), 11 patients (12.7%) received APs following CSF testing. Patients with Aβ42 below the median had sooner time-to-AP use. This was significant on a log-rank test (p  = 0.04). There was no difference in time-to-AP use if the group was stratified by levels of total tau, phosphorylated tau, or amyloid-to-tau index. Conclusion: These results suggest a relationship between lower CSF Aβ42 levels and sooner AP use. This supports prior reports suggesting a correlation between BPSD and Aβ deposition on PET. These results highlight the need for further prospective studies on Aβ levels and BPSD. Show more

Keywords: Alzheimer’s disease, antipsychotic agents, behavioral and psychological symptoms of dementia, biomarkers, dementia, neurodegenerative disease

DOI: 10.3233/ADR-220064

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 641-647, 2023

Authors: Saiyed, Nazia | Yilmaz, Ali | Vishweswariah, Sangeetha | Maiti, Amit K. | Ustun, Ilyas | Bartolone, Sarah | Brown-Hughes, Travonia | Thorpe Jr , Roland J. | Osentoski, Tammy | Ruff, Stacey | Pai, Amita | Maddens, Michael | Imam, Khaled | Graham, Stewart F.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia, accounting for 80% of all cases. Mild cognitive impairment (MCI) is a transitional state between normal aging and AD. Early detection is crucial, as irreversible brain damage occurs before symptoms manifest. Objective: This study aimed to identify potential biomarkers for early detection of AD by analyzing urinary cytokine concentrations. We investigated 37 cytokines in AD, MCI, and cognitively normal individuals (NC), assessing their associations with AD development. Methods: Urinary cytokine concentrations were measured in AD (n  = 25), MCI (n  = 25), and NC (n  = 26) patients. …IL6ST and MMP-2 levels were compared between AD and NC, while TNFRSF8, IL6ST, and IL-19 were assessed in AD versus MCI. Diagnostic models distinguished AD from NC, and in-silico analysis explored molecular mechanisms related to AD. Results: Significant perturbations in IL6ST and MMP-2 concentrations were observed in AD urine compared to NC, suggesting their potential as biomarkers. TNFRSF8, IL6ST, and IL-19 differed significantly between AD and MCI, implicating them in disease progression. Diagnostic models exhibited promising performance (AUC: 0.59–0.79, sensitivity: 0.72–0.80, specificity: 0.56–0.78) in distinguishing AD from NC. In-silico analysis revealed molecular insights, including relevant non-coding RNAs, microRNAs, and transcription factors. Conclusion: This study establishes significant associations between urinary cytokine concentrations and AD and MCI. IL6ST, MMP-2, TNFRSF8, IL6ST, and IL-19 emerge as potential biomarkers for early detection of AD. In-silico analysis enhances understanding of molecular mechanisms in AD. Further validation and exploration of these biomarkers in larger cohorts are warranted to assess their clinical utility. Show more

Keywords: Alzheimer’s disease, biomarkers, cytokines, inflammation, mild cognitive impairment, urine

DOI: 10.3233/ADR-220081

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 649-657, 2023

Authors: Roth, Sophie | Burnie, Nerida | Suridjan, Ivonne | Yan, Jessie T. | Carboni, Margherita

Article Type: Research Article

Abstract: Background: Diagnostic pathways for patients presenting with cognitive complaints may vary across geographies. Objective: To describe diagnostic pathways of patients presenting with cognitive complaints across 6 countries. Methods: This real-world, cross-sectional study analyzed chart-extracted data from healthcare providers (HCPs) for 6,744 patients across China, France, Germany, Spain, UK, and the US. Results: Most common symptoms at presentation were cognitive (memory/amnestic; 89.86%), followed by physical/behavioral (87.13%). Clinical/cognitive tests were used in > 95%, with Mini-Mental State Examination being the most common cognitive test (79.0%). Blood tests for APOE ɛ4/other mutations, or to rule out treatable causes, …were used in half of the patients. Clinical and cognitive tests were used at higher frequency at earlier visits, and amyloid PET/CSF biomarker testing at higher frequency at later visits. The latter were ordered at low rates even by specialists (across countries, 5.7% to 28.7% for amyloid PET and 5.0% to 27.3% for CSF testing). Approximately half the patients received a diagnosis (52.1% of which were Alzheimer’s disease [AD]). Factors that influenced risk of not receiving a diagnosis were HCP type (higher for primary care physicians versus specialists) and region (highest in China and Germany). Conclusion: These data highlight variability in AD diagnostic pathways across countries and provider types. About 45% of patients are referred/told to ‘watch and wait’. Improvements can be made in the use of amyloid PET and CSF testing. Efforts should focus on further defining biomarkers for those at risk for AD, and on dismantling barriers such low testing capacity and reimbursement challenges. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, diagnosis, neurology, neuropsychological tests, standard of care, surveys and questionnaires

DOI: 10.3233/ADR230007

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 659-674, 2023

Authors: Fotuhi, Majid | Khorrami, Noah D. | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Non-pharmacologic interventions can potentially improve cognitive function, sleep, and/or mood in patients with attention-deficit/hyperactive disorder (ADHD), post-concussion syndrome (PCS), or memory loss. Objective: We evaluated the benefits of a brain rehabilitation program in an outpatient neurology practice that consists of targeted cognitive training, lifestyle coaching, and electroencephalography (EEG)-based neurofeedback, twice weekly (90 minutes each), for 12 weeks. Methods: 223 child and adult patients were included: 71 patients with ADHD, 88 with PCS, and 64 with memory loss (mild cognitive impairment or subjective cognitive decline). Patients underwent a complete neurocognitive evaluation, including tests for Verbal Memory, …Complex Attention, Processing Speed, Executive Functioning, and Neurocognition Index. They completed questionnaires about sleep, mood, diet, exercise, anxiety levels, and depression—as well as underwent quantitative EEG—at the beginning and the end of the program. Results: Pre-post test score comparison demonstrated that all patient subgroups experienced statistically significant improvements on most measures, especially the PCS subgroup, which experienced significant score improvement on all measures tested (p ≤0.0011; d z ≥0.36). After completing the program, 60% to 90% of patients scored higher on cognitive tests and reported having fewer cognitive and emotional symptoms. The largest effect size for pre-post score change was improved executive functioning in all subgroups (ADHD d z = 0.86; PCS d z = 0.83; memory d z = 1.09). Conclusion: This study demonstrates that a multimodal brain rehabilitation program can have benefits for patients with ADHD, PCS, or memory loss and supports further clinical trials in this field. Show more

Keywords: Alzheimer’s disease, attention-deficit/hyperactivity disorder, electroencephalography, memory, neurofeedback, post-concussion syndrome, rehabilitation, subjective cognitive decline, subjective cognitive impairment, traumatic brain injury

DOI: 10.3233/ADR-220091

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 675-697, 2023

Authors: Guarnera, Jade | Yuen, Eva | Macpherson, Helen

Article Type: Review Article

Abstract: Social concepts such as loneliness and social isolation are fairly new factors that have been recently gaining attention as to their involvement in changes in cognitive function and association with dementia. The primary aim of this narrative review was to describe the current understanding of how loneliness and social isolation influence cognitive aging and how they are linked to dementia. Studies have shown that there is an association between loneliness, social isolation, and reduced cognitive function, in older adults, across multiple cognitive domains, as well as a heightened risk of dementia. Numerous changes to underlying neural biomechanisms including cortisol secretion …and brain volume alterations (e.g., white/grey matter, hippocampus) may contribute to these relationships. However, due to poor quality research, mixed and inconclusive findings, and issues accurately defining and measuring loneliness and social isolation, more consistent high-quality interventions are needed to determine whether studies addressing loneliness and social isolation can impact longer term risk of dementia. This is especially important given the long-term impact of the COVID-19 pandemic on social isolation in older people is yet to be fully understood. Show more

Keywords: Aging, alzheimer’s disease, cognition, dementia, loneliness, social isolation

DOI: 10.3233/ADR-230011

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 699-714, 2023

Authors: Michaelian, Johannes C. | McCade, Donna | Hoyos, Camilla M. | Brodaty, Henry | Harrison, Fleur | Henry, Julie D. | Guastella, Adam J. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Individuals living with Alzheimer’s disease (AD) demonstrate extensive deficits in social cognition. To date, no studies have investigated the feasibility of an intranasal oxytocin (INOT) treatment to improve social cognition in individuals living with AD. Objective: We conducted a pilot trial to determine recruitment feasibility, enrolment acceptability, and adherence to an INOT treatment to inform on the subsequent design of a future randomized controlled trial (RCT). We also estimated the effect sizes of potential social cognitive function outcome measures related to participants and their caregivers. Methods: Four individuals with AD were enrolled in a single-center, …randomized, double-blind, placebo-controlled crossover trial involving a one-week treatment period with both INOT (72 IU twice daily) and placebo. Results: All participants reported no treatment-causative or serious adverse events following repeated INOT administration. While enrolment acceptability (100%) and INOT adherence (placebo, 95%; INOT, 98%) were excellent, feasibility of recruitment was not acceptable (i.e., n  = 4/58 individuals screened met inclusion criteria). However, positive/large effects were associated with secondary outcomes of self-reported health and wellbeing, caregiver ‘burden’, intimacy and interpersonal-bonding, following repeated INOT administration. No positive effects were associated with participant outcomes of social cognition. Conclusion: This pilot RCT provides first evidence that INOT administration in individuals living with AD is safe and well-tolerated. Despite limitations in sample size, moderate-to-large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and ‘burden’ as reported by a caregiver. This suggests potential broad-ranging beneficial effects of INOT which should be assessed in future RCTs. Show more

Keywords: Alzheimer’s disease, dementia, intranasal oxytocin, oxytocin nasal spray, social cognition

DOI: 10.3233/ADR-230013

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 715-729, 2023

Authors: Takechi, Hajime | Yoshino, Hiroshi

Article Type: Research Article

Abstract: Background: As the number of patients with dementia increases, so do the social costs. In recent years, attempts have been made to reduce risk to be dementia and treat it from the early stages of the disease, making it important to estimate the costs of the early stages. Objective: To estimate the medical and social costs of the early stages of Alzheimer’s disease (AD), which include mild cognitive impairment (MCI) due to AD and mild AD. Methods: Questionnaires were used to obtain basic information (e.g., age, cognitive function) and medical costs, social care costs, family caregiver …medical costs, and family caregiver informal care costs from patients with MCI due to AD or mild AD who were attending a memory clinic. A comparison was then conducted between these two groups. Results: Patients with mild AD had higher total costs, patient medical costs, patient social care costs, and family caregiver informal care costs than did patients with MCI; however, only patient medical costs were significantly different (p  = 0.022). A detailed analysis of patient medical costs revealed that anti-dementia drug treatment costs were significantly higher in patients with mild AD (p  <  0.001). Conclusion: Compared with patients with mild AD, those with MCI may have lower patient and family caregiver costs. As it is important to reduce social costs through risk reduction and therapeutic interventions from the early stages of AD, the present findings could help estimate the social costs and verify the cost-effectiveness of early interventions for AD. Show more

Keywords: Alzheimer’s disease, caregiver, cost, dementia, mild cognitive impairment, resource use

DOI: 10.3233/ADR-230032

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 731-738, 2023

Authors: Keleman, Audrey A. | Nicosia, Jessica | Bollinger, Rebecca M. | Wisch, Julie K. | Hassenstab, Jason | Morris, John C. | Ances, Beau M. | Balota, David A. | Stark, Susan L.

Article Type: Research Article

Abstract: Background: Individuals with Alzheimer’s disease (AD) are more than twice as likely to incur a serious fall as the general population of older adults. Although AD is commonly associated with cognitive changes, impairments in other clinical measures such as strength or functional mobility (i.e., gait and balance) may precede symptomatic cognitive impairment in preclinical AD and lead to increased fall risk. Objective: To examine mechanisms (i.e., functional mobility, cognition, AD biomarkers) associated with increased falls in cognitively normal older adults. Methods: This 1-year study was part of an ongoing longitudinal cohort study. We examined the relationships …among falls, clinical measures of functional mobility and cognition, and neuroimaging AD biomarkers in cognitively normal older adults. We also investigated which domain(s) best predicted fall propensity and severity through multiple regression models. Results: A total of 182 older adults were included (mean age 75 years, 53% female). A total of 227 falls were reported over the year; falls per person ranged from 0–16 with a median of 1. Measures of functional mobility were the best predictors of fall propensity and severity. Cognition and AD biomarkers were associated with each other but not with the fall outcome measures. Conclusion: These results suggest that, although subtle changes in cognition may be more closely associated with AD neuropathology, functional mobility indicators better predict falls in cognitively normal older adults. This study adds to our understanding of the mechanisms underlying falls in older adults and could lead to the development of targeted fall prevention strategies. Show more

Keywords: Alzheimer’s disease, cognition, falls, functional mobility

DOI: 10.3233/ADR-230002

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 739-750, 2023

Authors: de la Monte, Suzanne M. | Goel, Anuva | Tong, Ming | Delikkaya, Busra

Article Type: Research Article

Abstract: Background: Agent Orange, an herbicide used during the Vietnam War, contains 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Agent Orange has teratogenic and carcinogenic effects, and population-based studies suggest Agent Orange exposures lead to higher rates of toxic and degenerative pathologies in the peripheral and central nervous system (CNS). Objective: This study examines the potential contribution of Agent Orange exposures to neurodegeneration. Methods: Human CNS-derived neuroepithelial cells (PNET2) treated with 2,4-D and 2,4,5-T were evaluated for viability, mitochondrial function, and Alzheimer’s disease (AD)-related proteins. Results: Treatment with 250μg/ml 2,4-D or 2,4,5-T significantly impaired mitochondrial …function, caused degenerative morphological changes, and reduced viability in PNET2 cells. Correspondingly, glyceraldehyde-3-phosphate dehydrogenase expression which is insulin-regulated and marks the integrity of carbohydrate metabolism, was significantly inhibited while 4-hydroxy-2-nonenal, a marker of lipid peroxidation, was increased. Tau neuronal cytoskeletal protein was significantly reduced by 2,4,5-T, and relative tau phosphorylation was progressively elevated by 2,4,5-T followed by 2,4-D treatment relative to control. Amyloid-β protein precursor (AβPP) was increased by 2,4,5-T and 2,4-D, and 2,4,5-T caused a statistical trend (0.05 < p<0.10) increase in Aβ. Finally, altered cholinergic function due to 2,4,5-T and 2,4-D exposures was marked by significantly increased choline acetyltransferase and decreased acetylcholinesterase expression, corresponding with responses in early-stage AD. Conclusion: Exposures to Agent Orange herbicidal chemicals rapidly damage CNS neurons, initiating a path toward AD-type neurodegeneration. Additional research is needed to understand the permanency of these neuropathologic processes and the added risks of developing AD in Agent Orange-exposed aging Vietnam Veterans. Show more

Keywords: Agent Orange, Alzheimer’s disease, herbicide, neurodegeneration, neurons, pesticide, Veterans, Vietnam, 2, 4-D, 2, 4, 5-T

DOI: 10.3233/ADR-230046

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 751-766, 2023

Authors: Morrow, Christopher B. | Leoutsakos, Jeannie | Yan, Haijuan | Onyike, Chiadi | Kamath, Vidyulata

Article Type: Short Communication

Abstract: Weight changes, neuropsychiatric symptoms (NPS), and cognitive decline often coincide in Alzheimer’s disease (AD) and frontotemporal dementia (FTD); however, the direction of their relationship remains unclear. This study aims to clarify the connection between weight changes, NPS, and cognition in AD and FTD. We found that cognitive decline was associated with decreased body mass index (BMI) in AD, while BMI gain was associated with increased conversion to FTD. Elevated NPS were associated with decreased BMI in AD and increased BMI in FTD. Identifying early changes in NPS and BMI may facilitate the detection of cognitive decline, providing an opportunity for …early intervention. Show more

Keywords: Alzheimer’s disease, body mass index, cognition, cognitive decline, frontotemporal dementia, neuropsychiatric symptoms, weight changes

DOI: 10.3233/ADR-230034

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 767-774, 2023

Authors: Tran, Todd | Finlayson, Marcia | Nalder, Emily | Trothen, Tracy | Donnelly, Catherine

Article Type: Research Article

Abstract: Background: Community-dwelling older adults with early cognitive deficits experience less efficiency in performing everyday life tasks, resulting in decreased satisfaction and other adverse psychological outcomes. Mindfulness training has been linked to cognitive and psychological improvements and, most recently, has been identified as a potential intervention supporting performance of everyday life activities. Objective: This study aimed to evaluate whether mindfulness practice can improve perceived performance and satisfaction with everyday life activity and secondary psychological outcomes. Methods: This study is a pilot randomized controlled trial (RCT) in an interprofessional primary care team practice in Toronto, Ontario, Canada. The …participants were 27 older adults aged 60 years of age or older living with early cognitive deficits. Participants were randomized into an 8-Week mindfulness training program (n  = 14) group or a Wait-List Control (WLC; n  = 13) group compared at baseline, post-intervention and 4-weeks follow-up. MANOVAs with post-hoc independent t-tests were used to compare between groups at different time points. Results: There was a significant improvement in anxiety for the intervention group compared to the WLC group at post-intervention; Time-2 (mean difference = 3.90; CI  = 0.04-7.75; p  = 0.04) with large effect size (d  = 0.80). Conclusion: Mindfulness training significantly improved anxiety scores for patients with early cognitive deficits post-intervention. Further work is required to test the sustainability of reduced anxiety over time, but this study demonstrated that MBSR is a promising primary care intervention for those living with early cognitive deficits. This study warrants the pursuit of a future study in exploring how long the reduced anxiety effects would be sustained. Show more

Keywords: Activities of daily living, Alzheimer’s disease, anxiety, health promotion, mild cognitive impairment, mindfulness meditation, occupational therapy, older adults, primary care, psychological outcomes, subjective cognitive decline

DOI: 10.3233/ADR-230006

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 775-790, 2023

Authors: Behera, Anindita | Sa, Nishigandha | Pradhan, Sweta Priyadarshini | Swain, Sunsita | Sahu, Pratap Kumar

Article Type: Review Article

Abstract: Nanotechnology has emerged in different fields of biomedical application, including lifestyle diseases like diabetes, hypertension, and chronic kidney disease, neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease, and different types of cancers. Metal nanoparticles are one of the most used drug delivery systems due to the benefits of their enhanced physicochemical properties as compared to bulk metals. Neurodegenerative diseases are the second most cause affecting mortality worldwide after cancer. Hence, they require the most specific and targeted drug delivery systems for maximum therapeutic benefits. Metal nanoparticles are the preferred drug delivery system, possessing greater blood-brain barrier permeability, biocompatibility, and enhanced …bioavailability. But some metal nanoparticles exhibit neurotoxic activity owing to their shape, size, surface charge, or surface modification. This review article has discussed the pathophysiology of AD. The neuroprotective mechanism of gold, silver, selenium, ruthenium, cerium oxide, zinc oxide, and iron oxide nanoparticles are discussed. Again, the neurotoxic mechanisms of gold, iron oxide, titanium dioxide, and cobalt oxide are also included. The neuroprotective and neurotoxic effects of nanoparticles targeted for treating AD are discussed elaborately. The review also focusses on the biocompatibility of metal nanoparticles for targeting the brain in treating AD. The clinical trials and the requirement to develop new drug delivery systems are critically analyzed. This review can show a path for the researchers involved in the brain-targeted drug delivery for AD. Show more

Keywords: Alzheimer’s disease, biocompatibility, clinical trials, metal nanoparticles, neuroprotective, neurotoxicity

DOI: 10.3233/ADR-220112

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 791-810, 2023

Authors: Wei, Tao | Shi, Xiaolei | Sun, Wei | Song, Weiyi | Zhou, Shaojiong | Zhao, Yiwei | Wang, Zhibin | Tang, Yi

Article Type: Research Article

Abstract: Background: Neurological disorders, such as Alzheimer’s disease (AD), comprise a major cause of health-related disabilities in human. However, biomarkers towards pathogenesis or novel targets are still limited. Objective: To identify the causality between plasma proteins and the risk of AD and other eight common neurological diseases using a Mendelian randomization (MR) study. Methods: Exposure data were obtained from a genome-wide association study (GWAS) of 2,994 plasma proteins in 3,301 healthy adults, and outcome datasets included GWAS summary statistics of nine neurological disorders. Inverse variance-weighted MR method as the primary analysis was used to estimate causal effects. …Results: Higher genetically proxied plasma myeloid cell surface antigen CD33 level was found to be associated with increased risk of AD (odds ratio [OR] 1.079, 95% confidence interval [CI] 1.047–1.112, p  = 8.39×10-7 ). We also discovered the causality between genetically proxied elevated prolactin and higher risk of epilepsy (OR = 1.068, 95% CI = 1.034–1.102; p  = 5.46×10-5 ). Negative associations were identified between cyclin-dependent kinase 8 and ischemic stroke (OR = 0.927, 95% CI = 0.896–0.959, p  = 9.32×10-6 ), between neuralized E3 ubiquitin-protein ligase 1 and migraine (OR = 0.914, 95% CI = 0.878–0.952, p  = 1.48×10-5 ), and between Fc receptor-like protein 4 and multiple sclerosis (MS) (OR = 0.929, 95% CI = 0.897–0.963, p  = 4.27×10-5 ). Conclusion: The findings identified MR-level protein-disease associations for AD, epilepsy, ischemic stroke, migraine, and MS. Show more

Keywords: Alzheimer’s disease, causality, Mendelian randomization, neurological disorders, plasma proteins

DOI: 10.3233/ADR-230058

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 811-822, 2023

Authors: Mehramiz, Mehrane | Porter, Tenielle | O’Brien, Eleanor K. | Rainey-Smith, Stephanie R. | Laws, Simon M.

Article Type: Review Article

Abstract: Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer’s disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing …the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-β and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia. Show more

Keywords: Alzheimer’s disease, dementia, lifestyle, SIRT1, sirtuin-1

DOI: 10.3233/ADR-220088

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 823-843, 2023

Authors: Fernandes, Mariana | Chiaravalloti, Agostino | Nuccetelli, Marzia | Placidi, Fabio | Izzi, Francesca | Camedda, Riccardo | Bernardini, Sergio | Sancesario, Giuseppe | Schillaci, Orazio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Research Article

Abstract: Background: Sleep impairment has been commonly reported in Alzheimer’s disease (AD) patients. The association between sleep dysregulation and AD biomarkers has been separately explored in mild cognitive impairment (MCI) and AD patients. Objective: The present study investigated cerebrospinal-fluid (CSF) and 18 F-fluoro-deoxy-glucose positron emission tomography (18 F-FDG-PET) biomarkers in MCI and AD patients in order to explore their association with sleep parameters measured with polysomnography (PSG). Methods: MCI and AD patients underwent PSG, 18 F-FDG-PET, and CSF analysis for detecting and correlating these biomarkers with sleep architecture. Results: Thirty-five patients were included in the …study (9 MCI and 26 AD patients). 18 F-FDG uptake in left Brodmann area 31 (owing to the posterior cingulate cortex) correlated negatively with REM sleep latency (p  = 0.013) and positively with REM sleep (p  = 0.033). 18 F-FDG uptake in the hippocampus was negatively associated with sleep onset latency (p  = 0.041). Higher CSF orexin levels were associated with higher sleep onset latency (p  = 0.042), Non-REM stage 1 of sleep (p  = 0.031), wake after sleep onset (p  = 0.028), and lower sleep efficiency (p  = 0.045). CSF levels of Aβ42 correlated negatively with the wake bouts index (p  = 0.002). CSF total-tau and phosphorylated tau levels correlated positively with total sleep time (p  = 0.045) and time in bed (p  = 0.031), respectively. Conclusion: Sleep impairment, namely sleep fragmentation, REM sleep dysregulation, and difficulty in initiating sleep correlates with AD biomarkers, suggesting an effect of sleep on the pathological processes in different AD stages. Targeting sleep for counteracting the AD pathological processes represents a timely need for clinicians and researchers. Show more

Keywords: Alzheimer’s disease, biomarkers, brain, cerebrospinal fluid, dementia, orexin, positron emission tomography, sleep

DOI: 10.3233/ADR-220111

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 845-854, 2023

Authors: Yu, Zhentao | Shi, Zhuoyu | Dan, Tingting | Dere, Mustafa | Kim, Minjeong | Li, Quefeng | Wu, Guorong

Article Type: Research Article

Abstract: Background: The AT[N] research framework focuses on three major biomarkers in Alzheimer’s disease (AD): amyloid-β deposition (A), pathologic tau (T), and neurodegeneration [N]. Objective: We hypothesize that the diverse mechanisms such as A⟶T and A⟶[N] pathways from one brain region to others, may underlie the wide variation in clinical symptoms. We aim to uncover the causal-like effect of regional AT[N] biomarkers on cognitive decline as well as the interaction with non-modifiable risk factors such as age and APOE4 . Methods: We apply multi-variate statistical inference to uncover all possible mechanistic spreading pathways through which the aggregation …of an upstream biomarker (e.g., increased amyloid level) in a particular brain region indirectly impacts cognitive decline, via the cascade build-up of a downstream biomarker (e.g., reduced metabolism level) in another brain region. Furthermore, we investigate the survival time for each identified region-to-region pathological pathway toward the AD onset. Results: We have identified a collection of critical brain regions on which the amyloid burdens exert an indirect effect on the decline in memory and executive function (EF) domain, being mediated by the reduction of metabolism level at other brain regions. APOE4 status has been found not only involved in many A⟶N mechanistic pathways but also significantly contributes to the risk of developing AD. Conclusion: Our major findings include 1) the region-to-region A⟶N⟶MEM and A⟶N⟶MEM pathways exhibit distinct spatial patterns; 2) APOE4 is significantly associated with both direct and indirect effects on the cognitive decline while sex difference has not been identified in the mediation analysis. Show more

Keywords: Alzheimer’s disease, biomarkers, mediation analysis, multi-variate variable selection, pathogenesis mechanism

DOI: 10.3233/ADR-230081

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 855-872, 2023

Authors: Loeffler, David A.

Article Type: Review Article

Abstract: Immunotherapeutic efforts to slow the clinical progression of Alzheimer’s disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither Aβ vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable Aβ; phase III results released at that …time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab’s phase III trial revealed that primary and secondary end points had been met. Antibody binding to Aβ facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar Aβ, and binding of antibody-Aβ complexes to blood-brain barrier receptors. Antibody binding to Aβ in peripheral blood may also promote cerebral efflux of Aβ by a peripheral sink mechanism. According to the amyloid hypothesis, for Aβ targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of Aβ clearance, findings in AD trials involving Aβ vaccination, IVIG, and anti-Aβ monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the Aβ-clearing ability of monoclonal antibodies. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid hypothesis, antibodies, clearance, clinical trials, downstream effects, intravenous immunoglobulin

DOI: 10.3233/ADR-230025

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 873-899, 2023

Authors: Wang, Mengxue | Wang, Yanjuan | Wang, Zan | Ren, Qingguo

Article Type: Systematic Review

Abstract: Background: Cognitive impairment (CI) is an important extrapulmonary complication in patients with chronic obstructive pulmonary disease (COPD). Multimodal Neuroimaging Examination can display changes in brain structure and functions in patients with COPD. Objective: The purpose of this systematic review is to provide an overview of the variations in brain imaging in patients with COPD and their potential relationship with CI. Furthermore, we aim to provide new ideas and directions for future research. Methods: Literature searches were performed using the electronic databases PubMed, Scopus, and ScienceDirect. All articles published between January 2000 and November 2021 that met …the eligibility criteria were included. Results: Twenty of the 23 studies focused on changes in brain structure and function. Alterations in the brain’s macrostructure are manifested in the bilateral frontal lobe, hippocampus, right temporal lobe, motor cortex, and supplementary motor area. The white matter microstructural changes initially appear in the bilateral frontal subcortical region. Regarding brain function, patients with COPD exhibited reduced frontal cerebral perfusion and abnormal alterations in intrinsic brain activity in the bilateral posterior cingulate cortex, precuneus, right lingual gyrus, and left anterior central gyrus. Currently, there is limited research related to brain networks. Conclusion: CI in patients with COPD may present as a type of dementia different from Alzheimer’s disease, which tends to manifest as frontal cognitive decline early in the disease. Further studies are required to clarify the neurobiological pathways of CI in patients with COPD from the perspective of brain connectomics based on the whole-brain system in the future. Show more

Keywords: Alzheimer’s disease, brain imaging, chronic obstructive pulmonary disease, cognitive impairment, mechanism

DOI: 10.3233/ADR-220083

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 901-919, 2023

Authors: Volloch, Vladimir | Rits-Volloch, Sophia

Article Type: Other

Abstract: With the Amyloid Cascade Hypothesis (ACH) largely discredited, the ACH2.0 theory of Alzheimer’s disease (AD) has been recently introduced. Within the framework of the ACH2.0, AD is triggered by amyloid-β protein precursor (AβPP)-derived intraneuronal Aβ (i Aβ) and is driven by i Aβ produced in the AβPP-independent pathway and retained intraneuronally. In this paradigm, the depletion of extracellular Aβ or suppression of Aβ production by AβPP proteolysis, the two sources of AβPP-derived i Aβ, would be futile in symptomatic AD, due to its reliance on i Aβ generated independently of AβPP, but effective in preventing AD and treating Aging-Associated …Cognitive Decline (AACD) driven, in the ACH2.0 framework, by AβPP-derived i Aβ. The observed effect of lecanemab and donanemab, interpreted in the ACH2.0 perspective, supports this notion and mandates AD-preventive clinical trials. Such trials are currently in progress. They are likely, however, to fail or to yield deceptive results if conducted conventionally. The present study considers concepts of design of clinical trials of lecanemab, donanemab, or any other drug, targeting the influx of AβPP-derived i Aβ, in prevention of AD and treatment of AACD. It analyzes possible outcomes and explains why selection of high-risk asymptomatic participants seems reasonable but is not. It argues that outcomes of such AD preventive trials could be grossly misleading, discusses inevitable potential problems, and proposes feasible solutions. It advocates the initial evaluation of this type of drugs in clinical trials for treatment of AACD. Whereas AD protective trials of these drugs are potentially of an impractical length, AACD clinical trials are expected to yield unequivocal results within a relatively short duration. Moreover, success of the latter, in addition to its intrinsic value, would constitute a proof of concept for the former. Furthermore, this study introduces concepts of the active versus passive i Aβ depletion, contends that targeted degradation of i Aβ is the best therapeutic strategy for both prevention and treatment of AD and AACD, proposes potential i Aβ-degrading drugs, and describes their feasible and unambiguous evaluation in clinical trials. Show more

Keywords: Aging-associated cognitive decline, Alzheimer’s disease, Amyloid Cascade Hypothesis 2.0 (ACH2.0), BACE1 and BACE2 activators, clinical trial design, donanemab, intraneuronal Aβ , lecanemab, verubecestat

DOI: 10.3233/ADR-230037

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 921-955, 2023

Authors: Patel, Ashay O. | Caldwell, Andrew B. | Ramachandran, Srinivasan | Subramaniam, Shankar

Article Type: Research Article

Abstract: Background: While Alzheimer’s disease (AD) pathology is associated with altered brain structure, it is not clear whether gene expression changes mirror the onset and evolution of pathology in distinct brain regions. Deciphering the mechanisms which cause the differential manifestation of the disease across different regions has the potential to help early diagnosis. Objective: We aimed to identify common and unique endotypes and their regulation in tangle-free neurons in sporadic AD (SAD) across six brain regions: entorhinal cortex (EC), hippocampus (HC), medial temporal gyrus (MTG), posterior cingulate (PC), superior frontal gyrus (SFG), and visual cortex (VCX). Methods: …To decipher the states of tangle-free neurons across different brain regions in human subjects afflicted with AD, we performed analysis of the neural transcriptome. We explored changes in differential gene expression, functional and transcription factor target enrichment, and co-expression gene module detection analysis to discern disease-state transcriptomic variances and characterize endotypes. Additionally, we compared our results to tangled AD neuron microarray-based study and the Allen Brain Atlas. Results: We identified impaired neuron function in EC, MTG, PC, and VCX resulting from REST activation and reversal of mature neurons to a precursor-like state in EC, MTG, and SFG linked to SOX2 activation. Additionally, decreased neuron function and increased dedifferentiation were linked to the activation of SUZ12. Energetic deficit connected to NRF1 inactivation was found in HC, PC, and VCX. Conclusions: Our findings suggest that SAD manifestation varies in scale and severity in different brain regions. We identify endotypes, such as energetic shortfalls, impaired neuronal function, and dedifferentiation. Show more

Keywords: Alzheimer’s disease, dedifferentiation, endotype, energetics, NRF1, REST, SOX2, sporadic Alzheimer’s disease, SUZ12, transcriptome

DOI: 10.3233/ADR-220098

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 957-972, 2023

Authors: Yu, Ruan-Ching | Lai, Jen-Chieh | Hui, Esther K. | Mukadam, Naaheed | Kapur, Narinder | Stott, Joshua | Livingston, Gill

Article Type: Systematic Review

Abstract: Background: Chinese is the most commonly spoken world language; however, most cognitive tests were developed and validated in the West. It is essential to find out which tests are valid and practical in Chinese speaking people with suspected dementia. Objective: We therefore conducted a systematic review and meta-analysis of brief cognitive tests adapted for Chinese-speaking populations in people presenting for assessment of suspected dementia. Methods: We searched electronic databases for studies reporting brief (≤20 minutes) cognitive test’s sensitivity and specificity as part of dementia diagnosis for Chinese-speaking populations in clinical settings. We assessed …quality using Centre for Evidence Based Medicine (CEBM) criteria and translation and cultural adaptation using the Manchester Translation Reporting Questionnaire (MTRQ), and Manchester Cultural Adaptation Reporting Questionnaire (MCAR). We assessed heterogeneity and combined sensitivity in meta-analyses. Results: 38 studies met inclusion criteria and 22 were included in meta-analyses. None met the highest CEBM criteria. Five studies met the highest criteria of MTRQ and MCAR. In meta-analyses of studies with acceptable heterogeneity (I2  <  75%), Addenbrooke’s Cognitive Examination Revised &III (ACE-R & ACE-III) had the best sensitivity and specificity; specifically, for dementia (93.5% & 85.6%) and mild cognitive impairment (81.4% & 76.7%). Conclusions: Current evidence is that the ACE-R and ACE-III are the best brief cognitive assessments for dementia and mild cognitive impairment in Chinese-speaking populations. They may improve time taken to diagnosis, allowing people to access interventions and future planning. Show more

Keywords: Alzheimer’s disease, cognitive assessment, dementia, diagnosis, mild cognitive impairment

DOI: 10.3233/ADR-230024

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 973-987, 2023

Authors: Aborode, Abdullahi Tunde | Idowu, Nike Jesutofunmi | Tundealao, Samuel | Jaiyeola, Joseph | Ogunware, Adedayo Emmanuel

Article Type: Article Commentary

Abstract: This paper explores the emerging field of neuroscience in Africa, considering the unique genetic diversity, socio-cultural determinants, and health inequalities in the continent. It presents numerous brain research initiatives, such as ABDRN, AMARI, APCDR, and H3Africa, aimed at understanding genetic and environmental factors influencing brain disorders in Africa. Despite numerous challenges like the brain drain phenomenon, inadequate infrastructure, and scarce research expertise, significant progress has been achieved. The paper proposes solutions, including international collaboration, capacity-building efforts, and policies to promote neuroscience research, to enhance the understanding of brain function and address brain-related health issues within the African context.

Keywords: Africa, Alzheimer’s disease, brain drain, brain research, collaboration, global partnerships, health inequities, infrastructure, neuroscience, research capacity

DOI: 10.3233/ADR-230062

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 989-992, 2023

Authors: Kropf, Mario

Article Type: Research Article

Abstract: Dementia currently affects more than 55 million people worldwide, and scientists predict that this number will continue to rise. The most common form is Alzheimer’s disease (AD), which is triggered, among other things, by dysfunctional cells in the human brain. Stem cell research attempts to counteract neurodegenerative processes, for example by replacing or treating diseased cells. In addition to human embryonic stem cells, since the successes of Takahashi and Yamanaka in 2006, there has been an increased focus on human induced pluripotent stem cells (hiPS cells). These cells avoid ethically challenging questions about the moral status of human embryos, but …there are numerous problems, such as high production costs, side effects from the reprogramming process, or a potentially new moral status. These ethical issues will be examined primarily in relation to AD. The first part will be a discussion of hiPS cells and their importance for stem cell research, after which the focus turns to AD. Based on scientific studies, the relationship between hiPS cells and AD will be outlined as well as ethical implications presented. While potential limitations of hiPS cells have been discussed by numerous authors, an ethical perspective on the link between hiPS cells and AD seems to be neglected in the scientific community. The following risk analysis aims to identify a possible research agenda. In conclusion, the focus on individuals with AD may help to adopt an ethical stance that recognizes existing limitations and constructively engages with the possibilities of research. Show more

Keywords: Alzheimer’s disease, ethics, human induced pluripotent stem cells, moral issues, stem cells

DOI: 10.3233/ADR-230018

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 993-1006, 2023

Authors: Alves-Borba, Laryssa | Espinosa-Fernández, Verónica | Canseco-Rodríguez, Ania | Sánchez-Pérez, Ana María

Article Type: Short Communication

Abstract: Insulin resistance underlies Alzheimer’s disease (AD) by affecting neuroinflammation and brain-derived neurotrophic factor (BDNF) expression. Here, we evaluated the effect of early and late-start abscisic acid (ABA) intervention on hippocampal BDNF, tumor necrosis factor α (TNFα), and insulin receptors substrates (IRS) 1/2 mRNA levels in a triple-transgenic mice model of AD. Transgenic mice displayed lower BDNF and IRS2, equal IRS1, and higher TNFα expression compared to wild-type mice. Late ABA treatment could rescue TNFα and increased IRS1/2 expression. However, early ABA administration was required to increase BDNF expression. Our data suggests that early intervention with ABA can prevent AD, via …rescuing IRS1/2 and BDNF expression. Show more

Keywords: Alzheimer’s disease, hippocampus, insulin signal, neuroinflammation, neuroprotector, neurotrophic factor, phytohormones

DOI: 10.3233/ADR-230056

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1007-1013, 2023

Authors: Willis, Brian A. | Lo, Albert C. | Dage, Jeffrey L. | Shcherbinin, Sergey | Chinchen, Louise | Andersen, Scott W. | LaBell, Elizabeth S. | Perahia, David G.S. | Hauck, Paula M. | Lowe, Stephen L.

Article Type: Research Article

Abstract: Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer’s disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. …Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed. Clinicaltrials.gov: NCT03019536 Show more

Keywords: Aggregated tau, Alzheimer’s disease, antibody, safety pharmacokinetics, zagotenemab

DOI: 10.3233/ADR-230012

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1015-1024, 2023

Authors: Franks, Katherine H. | Cribb, Lachlan | Bransby, Lisa | Buckley, Rachel | Yassi, Nawaf | Chong, Trevor T.-J. | Lim, Yen Ying | Pase, Matthew P.

Article Type: Short Communication

Abstract: Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-β42 , phosphorylated tau-181, total tau, or neurofilament light chain. Cohen’s f2 effect sizes were small in magnitude (f2 ≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels …of stress. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, psychological stress

DOI: 10.3233/ADR-230052

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1025-1031, 2023

Authors: Zhou, Aoshuang | Britt, Carlene | Woods, Robyn L. | Orchard, Suzanne G. | Murray, Anne M. | Shah, Raj C. | Rajan, Ramesh | McNeil, John J. | Chong, Trevor T.-J. | Storey, Elsdon | Ryan, Joanne

Article Type: Research Article

Abstract: Background: The Controlled Oral Word Association Test (COWAT) is a commonly used measure of verbal fluency. While a normal decline in verbal fluency occurs in late adulthood, significant impairments may indicate brain injury or diseases such as Alzheimer’s disease. Normative data is essential to identify when test performance falls below expected levels based on age, gender, and education level. Objective: This study aimed to establish normative performance data on single-letter COWAT for older community-dwelling adults. Methods: Over 19,000 healthy men and women, without a diagnosis of dementia or a Modified Mini-Mental State Examination score below 77/100, …were recruited for the ASPREE trial. Neuropsychological assessments, including the COWAT with letter F, were administered at study entry. Results: Median participant age was 75 years (range 65–98), with 56.5% being women. The majority of participants had 9–11 years of education in Australia and over 12 years in the U.S. The COWAT performance varied across ethno-racial groups and normative data were thus presented separately for 16,335 white Australians, 1,084 white Americans, 896 African-Americans, and 316 Hispanic/Latinos. Women generally outperformed men in the COWAT, except for Hispanic/Latinos. Higher education levels consistently correlated with better COWAT performance across all groups, while the negative association with age was weaker. Conclusions: This study provides comprehensive normative data for the COWAT stratified by ethno-racial groups in Australia and the U.S., considering age, gender, and education level. These norms can serve as reference standards for screening cognitive impairments in older adults in both clinical and research settings. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, normative data, phonemic fluency

DOI: 10.3233/ADR-230089

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1033-1043, 2023

Authors: Xiao, Qing | Li, Yonggang | Li, Benchao | Li, Tingting | Li, Fengping | Li, Yuanyuan | Chen, Liangkai | Zhao, Zhuangju | Wang, Qing | Rong, Shuang

Article Type: Research Article

Abstract: Background: The evidence concerning dietary diversity and cognitive function remains insufficient. Objective: To investigate the association of dietary diversity score (DDS) with mild cognitive impairment (MCI) and cognitive performance in different domains. Methods: Data from The Lifestyle and Healthy Aging of Chinese Square Dancer Study was used in this study. DDS was constructed based on the intake frequencies of 9 food groups assessed by a validated food frequency questionnaire. MCI was diagnosed by Petersen’s criteria. A neuropsychological test battery was used to assess the performance on cognitive domains, and test scores were standardized to Z scores. …Multiple linear regression models and logistic regression models were used to estimate the β and odds ratios and their 95% CIs, respectively. Results: Among 1,982 participants, the mean (SD) age was 63.37 (5.00) years, 1,778 (89.71%) were women, and 279 (14.08%) had MCI. Compared to the DDS quartile (0, 6], the multivariable-adjusted odds ratios (95% CI) were 0.74 (0.48, 1.15) for DDS quartile (6, 7], 0.65 (0.43, 0.97) for DDS quartile (7, 8], and 0.55 (0.37, 0.84) for DDS quartile (8, 9]. Furthermore, higher DDS was positively associated with better performance of cognitive domains, including global cognitive function (β= 0.20, 95% CI: 0.12, 0.30), episodic memory (β= 0.21, 95% CI: 0.07, 0.35), attention (β= 0.15, 95% CI: 0.03, 0.26), language fluency (β= 0.24, 95% CI: 0.10, 0.38), and executive function (β= – 0.24, 95% CI: – 0.38, – 0.10). Conclusions: This study indicated that higher DDS was associated with better cognitive function among middle-aged and older Chinese people. Show more

Keywords: Alzheimer’s disease, cognitive domains, cross-sectional study, dietary diversity, mild cognitive impairment

DOI: 10.3233/ADR-230060

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1045-1053, 2023

Authors: Teipel, Stefan J | Dyrba, Martin | Levin, Fedor | Altenstein, Slawek | Berger, Moritz | Beyle, Aline | Brosseron, Frederic | Buerger, Katharina | Burow, Lena | Dobisch, Laura | Ewers, Michael | Fliessbach, Klaus | Frommann, Ingo | Glanz, Wenzel | Goerss, Doreen | Gref, Daria | Hansen, Niels | Heneka, Michael T. | Incesoy, Enise I. | Janowitz, Daniel | Keles, Deniz | Kilimann, Ingo | Laske, Christoph | Lohse, Andrea | Munk, Matthias H. | Perneczky, Robert | Peters, Oliver | Preis, Lukas | Priller, Josef | Rostamzadeh, Ayda | Roy, Nina | Schmid, Matthias | Schneider, Anja | Spottke, Annika | Spruth, Eike Jakob | Wiltfang, Jens | Düzel, Emrah | Jessen, Frank | Kleineidam, Luca | Wagner, Michael

Article Type: Research Article

Abstract: Background: Cognitive decline is a key outcome of clinical studies in Alzheimer’s disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial …models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid. Show more

Keywords: Alzheimer’s disease, executive function, longitudinal, memory, mild cognitive impairment, non-linear, practice effects, subjective cognitive decline

DOI: 10.3233/ADR-230027

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1055-1076, 2023

Authors: Funayama, Michitaka | Kuramochi, Shin | Kudo, Shun

Article Type: Short Communication

Abstract: Diagnosing neurosyphilis can be challenging and it may be misdiagnosed as behavior variant frontotemporal dementia, given its affinity for the frontal and temporal lobes. Here we present a model case, who, in his 40 s, was initially misdiagnosed with behavioral variant frontotemporal dementia based on extreme self-neglect and disinhibition over six months and frontal lobe atrophy. He was later diagnosed as neurosyphilis with positive syphilis tests in his cerebrospinal fluid. He underwent penicillin treatment and fully recovered. Relatively rapid cognitive decline, particularly if young, should prompt physicians to consider neurosyphilis as a treatable dementia, which could completely change a patient’s life.

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, differential diagnosis, dysexecutive function, frontal lobe, neurosyphilis, treatable dementia

DOI: 10.3233/ADR-230107

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1077-1083, 2023

Authors: Sagalajev, Boriss | Lennartz, Lina | Vieth, Lukas | Gunawan, Cecilia Tasya | Neumaier, Bernd | Drzezga, Alexander | Visser-Vandewalle, Veerle | Endepols, Heike | Sesia, Thibaut

Article Type: Research Article

Abstract: Background: The TgF344-AD ratline represents a transgenic animal model of Alzheimer’s disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance. Methods: TgF344-AD rats were divided into two groups balanced by sex and genotype. The first …group underwent the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14–16 months old during DMS testing and PET. Results: In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats. Conclusions: TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with past clinical research. In rats with preserved spatial orientation, working memory remains intact. Show more

Keywords: Alzheimer’s disease, brain imaging, glucose, microglia, PET, rat model, spatial orientation, working memory

DOI: 10.3233/ADR-230038

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1085-1094, 2023

Authors: Roe, Catherine M. | Bayat, Sayeh | Babulal, Ganesh M.

Article Type: Research Article

Abstract: Background: Declines in instrumental activities of daily living like driving are hallmarks sequelae of Alzheimer’s disease (AD). Although driving has been shown to be associated with traditional imaging and cerebrospinal fluid (CSF) biomarkers, it is possible that some biomarkers have stronger associations with specific aspects of driving behavior. Furthermore, associations between newer plasma biomarkers and driving behaviors are unknown. Objective: This study assessed the extent to which individual plasma, imaging, and CSF biomarkers are related to specific driving behaviors and cognitive functions among cognitively normal older adults. Methods: We analyzed naturalistic driving behavior from cognitively healthy …older drivers (N = 167, 47% female, mean age = 73.3 years). All participants had driving, clinical, and demographic data and completed biomarker testing, including imaging, CSF, and/or plasma, within two years of study commencement. Results: AD biomarkers were associated with different characteristics of driving and cognitive functioning within the same individuals. Elevated levels of plasma Aβ40 were associated with more speeding incidents, higher levels of CSF tau were related to shorter duration of trips, and higher CSF neurofilament light chain values were associated with traveling shorter distances, smaller radius of gyration, and fewer trips at night. We demonstrated that plasma, like CSF and imaging biomarkers, were helpful in predicting everyday driving behaviors. Conclusions: These findings suggest that different biomarkers offer complementary information with respect to driving behaviors. These distinct relationships may help in understanding how different biological changes that occur during the preclinical stage of AD can impact various sensorimotor and cognitive processes. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, imaging, naturalistic driving

DOI: 10.3233/ADR-230088

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1095-1102, 2023

Authors: Siriwardhana, Chathura | Carrazana, Enrique | Liow, Kore | Chen, John J.

Article Type: Research Article

Abstract: Background: There is an expanding body of literature implicating heart disease and stroke as risk factors for Alzheimer’s disease (AD). Hawaii is one of the six majority-minority states in the United States and has significant racial health disparities. The Native-Hawaiians/Pacific-Islander (NHPI) population is well-known as a high-risk group for a variety of disease conditions. Objective: We explored the association of cardiovascular disease with AD development based on the Hawaii Medicare data, focusing on racial disparities. Methods: We utilized nine years of Hawaii Medicare data to identify subjects who developed heart failure (HF), ischemic heart disease (IHD), …atrial fibrillation (AF), acute myocardial infarction (AMI), stroke, and progressed to AD, using multistate models. Propensity score-matched controls without cardiovascular disease were identified to compare the risk of AD after heart disease and stroke. Racial/Ethnic differences in progression to AD were evaluated, accounting for other risk factors. Results: We found increased risks of AD for AF, HF, IHD, and stroke. Socioeconomic (SE) status was found to be critical to AD risk. Among the low SE group, increased AD risks were found in NHPIs compared to Asians for all conditions selected and compared to whites for HF, IHD, and stroke. Interestingly, these observations were found reversed in the higher SE group, showing reduced AD risks for NHPIs compared to whites for AF, HF, and IHD, and to Asians for HF and IHD. Conclusions: NHPIs with poor SE status seems to be mostly disadvantaged by the heart/stroke and AD association compared to corresponding whites and Asians. Show more

Keywords: Alzheimer’s disease, heart disease, racial groups, stroke

DOI: 10.3233/ADR-230003

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1103-1120, 2023

Authors: Swerdlow, Russell H. | Jawdat, Omar | Swint-Kruse, Liskin | Townley, Ryan

Article Type: Case Report

Abstract: Fused in sarcoma (FUS) mutations cause frontotemporal dementia (FTD) and motor neuron disease (MND). Here, we describe a 43-year-old man with progressive behavioral and cognitive change, myelopathy, clinical and electrophysiologic evidence of MND, and a FUS variant of unknown significance (VUS). This VUS, a heterozygous G559A transition (Gly187Ser), was previously reported in a patient with sporadic MND and affects important FUS biophysical properties. While this rare variant’s presence in a second patient with a related neurodegenerative syndrome does not establish pathogenicity, it raises the question of whether its association with our patient is coincidental and increases the possibility that FUS …G559A is pathogenic. Show more

Keywords: Case report, frontotemporal dementia, FUS, motor neuron disease

DOI: 10.3233/ADR-230103

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1121-1126, 2023

Authors: Wang, Jing-Juan | Zhang, Qiao-Feng | Liu, Di | Du, Qing | Xu, Cheng | Wu, Quan-Xin | Tang, Yi | Jin, Wang-Sheng

Article Type: Research Article

Abstract: Background: The acute stage of COVID-19 often presents with neurological manifestations. Objective: This study aims to investigate the long-term neurological effects on survivors. Methods: This study recruited 1,546 COVID-19 survivors from Wuhan, including 1,119 nonsevere cases and 427 severe survivors. Participants were interviewed two years after discharge to report their neurological symptoms. The neurological symptoms of COVID-19 were compared between survivors of severe and nonsevere COVID-19. Results: Among the 1,546 COVID-19 survivors, 44.24% discovered at least one neurological symptom. The most prevalent self-reported symptom was fatigue (28.33%), memory deficit (13.26%), attention deficit (9.96%), myalgia …(8.34%), dizziness (3.82%), and headache (2.52%). Severe cases had higher incidences of fatigue, myalgia, memory deficit, attention deficit than nonsevere cases. Older age, severe COVID-19, and comorbidity burden were associated with long-term neurological symptoms. Conclusion: Neurological symptoms are common among COVID-19 survivors, especially in severe cases. Show more

Keywords: COVID-19, long-COVID, neurological symptoms, sequelae

DOI: 10.3233/ADR-230078

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1127-1132, 2023

Authors: Marefat, Haniyeh | Vahabi, Zahra | Afzalian, Neda | Khanbagi, Mahdiyeh | Karimi, Hamed | Ebrahiminia, Fatemeh | Kalafatis, Chris | Modarres, Mohammad Hadi | Khaligh-Razavi, Seyed-Mahdi

Article Type: Research Article

Abstract: Background: In early Alzheimer’s disease (AD), high-level visual functions and processing speed are impacted. Few functional magnetic resonance imaging (fMRI) studies have investigated high-level visual deficits in AD, yet none have explored brain activity patterns during rapid animal/non-animal categorization tasks. Objective: To address this, we utilized the previously known Integrated Cognitive Assessment (ICA) to collect fMRI data and compare healthy controls (HC) to individuals with mild cognitive impairment (MCI) and mild AD. Methods: The ICA encompasses a rapid visual categorization task that involves distinguishing between animals and non-animals within natural scenes. To comprehensively explore variations in …brain activity levels and patterns, we conducted both univariate and multivariate analyses of fMRI data. Results: The ICA task elicited activation across a range of brain regions, encompassing the temporal, parietal, occipital, and frontal lobes. Univariate analysis, which compared responses to animal versus non-animal stimuli, showed no significant differences in the regions of interest (ROIs) across all groups, with the exception of the left anterior supramarginal gyrus in the HC group. In contrast, multivariate analysis revealed that in both HC and MCI groups, several regions could differentiate between animals and non-animals based on distinct patterns of activity. Notably, such differentiation was absent within the mild AD group. Conclusions: Our study highlights the ICA task’s potential as a valuable cognitive assessment tool designed for MCI and AD. Additionally, our use of fMRI pattern analysis provides valuable insights into the complex changes in brain function associated with AD. This approach holds promise for enhancing our understanding of the disease’s progression. Show more

Keywords: Alzheimer’s disease, high-level visual categorization, functional MRI, mild cognitive impairment, multivariate pattern analysis

DOI: 10.3233/ADR-230132

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1133-1152, 2023

Authors: Ma, Yuanyuan | Gong, Juan | Zeng, Lingli | Wang, Qinghua | Yao, Xiuqing | Li, Huiming | Chen, Yaozhi | Liu, Feng | Zhang, Mengyuan | Ren, Hui | Xiao, Lily Dongxia | Lian, Yan

Article Type: Research Article

Abstract: Background: As the primary caregivers for people with dementia in China, family caregivers face a significant care burden that can negatively impact their mental and physical health. It is vital to investigate ways to support these caregivers. Objective: To assess the effectiveness of a program led by community nurses to support caregivers of individuals with dementia. Methods: A total of 30 caregivers received nurse-led support in addition to usual care, while 28 caregivers received only usual care. The primary outcome was caregivers’ sense of competency in providing dementia care, which was measured using the Short Sense …of Competence Questionnaire (SSCQ). Secondary outcomes included caregivers’ ability to perform daily activities, behavioral and psychological symptoms of dementia (BPSD) using a neuropsychiatric inventory questionnaire, and quality of life using the short form health survey (SF-36). The trial was registered at the Chinese Clinical Trial Registry (ChiCTR 2300071484). Results: Compared to the control group, the intervention group had significantly higher SSCQ scores and a lower caregiver distress index over time. Physical and mental health-related quality of life also improved significantly among caregivers in the intervention group. However, there was no significant difference between the two groups in terms of activities of daily living and BPSD. Conclusions: The community nurse-led support program significantly improved caregivers’ competency in providing dementia care and quality of life and reduced distress. These findings have important implications for dementia care policies, resources, and workforce development in China, including strengthening community dementia care services through collaboration with specialists in hospitals. Show more

Keywords: Alzheimer’s disease, caregivers, community health nursing, community support, dementia

DOI: 10.3233/ADR-230067

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1153-1164, 2023

Authors: Tian, Jing | Du, Eric | Guo, Lan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a lethal neurodegenerative disorder characterized by severe brain pathologies and progressive cognitive decline. While the exact cause of this disease remains unknown, emerging evidence suggests that dysregulation of neurotransmitters contributes to the development of AD pathology and symptoms. Serotonin, a critical neurotransmitter in the brain, plays a pivotal role in regulating various brain processes and is implicated in neurological and psychiatric disorders, including AD. Recent studies have shed light on the interplay between mitochondrial function and serotonin regulation in brain physiology. In AD, there is a deficiency of serotonin, along with impairments in mitochondrial function, particularly …in serotoninergic neurons. Additionally, altered activity of mitochondrial enzymes, such as monoamine oxidase, may contribute to serotonin dysregulation in AD. Understanding the intricate relationship between mitochondria and serotonin provides valuable insights into the underlying mechanisms of AD and identifies potential therapeutic targets to restore serotonin homeostasis and alleviate AD symptoms. This review summarizes the recent advancements in unraveling the connection between brain mitochondria and serotonin, emphasizing their significance in AD pathogenesis and underscoring the importance of further research in this area. Elucidating the role of mitochondria in serotonin dysfunction will promote the development of therapeutic strategies for the treatment and prevention of this neurodegenerative disorder. Show more

Keywords: Alzheimer’s disease, mitochondria, neurobiology, pathogenesis, serotonin

DOI: 10.3233/ADR-230070

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1165-1177, 2023

Authors: Luque-Tirado, Andrea | Montiel-Herrera, Fátima | Maestre-Bravo, Rebeca | Barril-Aller, Claudia | García-Roldán, Ernesto | Arriola-Infante, José Enrique | Sánchez-Arjona, María Bernal | Rodrigo-Herrero, Silvia | Vargas-Romero, Juan Pedro | Franco-Macías, Emilio

Article Type: Research Article

Abstract: Background: The “Triana Test” is a novel story recall test based on emotional material with demonstrated accuracy in diagnosing mild cognitive impairment patients. Objective: This study aims to obtain normative data for the “Triana Test”. Methods: A normative study was conducted at a university hospital in Spain. Partners of patients were systematically recruited if eligible (age ≥50, no memory complaints, and a total TMA-93 score at or above the 10th percentile). The “Triana Test” was administered and scored. For developing the normative data, a regression-based method was followed. Results: The final sample included 362 …participants (median age = 66, range = 50–88; 64.9% females). A model including age and educational level better predicted the total scores. Combinations of these variables resulted in different 10th percentile scores. Conclusions: Norms for using the “Triana Test” are now available. The provided cutoffs for the 10th percentile will aid in the diagnosis of prodromal Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive assessment, emotional memory, neuropsychology, normative data

DOI: 10.3233/ADR-230096

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1179-1186, 2023

Authors: Gaber, Heba Ahmed | Aly, Eman Mohamed | Mohamed, Eman Saad | Elfoly, Marwa | Rabie, Mostafa Adel | Talaat, Mona Salah | El-Sayed, El-Sayed Mahmoud

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that progresses over time. Fourier Transform Infrared Spectroscopy (FTIR) analysis gives identification of the main metabolic changes that happen during neurodegeneration, by monitoring biochemical and molecular structure alterations that can help in AD diagnosis or treatment approach. Objective: The aim of the present work is to assess AD hallmarks in molecular structure of retina and monitor accumulation of amyloid beta42 (Aβ42 ) in brain and retina during disease progression. Methods: AD induced in rats by Aluminum Chloride (AlCl3 ). Retinal molecular structure during disease progression for 2,4,6 and …8 weeks was assessed by Fourier-transform infrared spectroscopy (FTIR) and the incidence of the disease was confirmed by a behavioural assessment; the Morris Water Maze test. Aβ42 levels in the brain and retina were also measured. Results: The results indicated that cognitive impairment starting from 6 weeks of AlCl3 administration. Retinal concentration of Aβ42 was significant increase (p  < 0.05) from 2 weeks that precedes the observed increase of Aβ42 in the brain which appeared after 4 weeks of AlCl3 administration. Multivariate principal component analysis discovers that the variance noticed in the infrared spectra due to AD condition and it is time dependent for progression of the disease. Conclusions: The accumulation of Aβ42 is a sensitive early biomarker in retina for AD. FTIR analysis of the retina revealed changes in hydrogen bond formation or destruction, alterations in lipid chain length and branching accompanied by depleted lipid content and carbonization, as well as degeneration of the retinal tissue due to AD. Show more

Keywords: Aluminum, Alzheimer’s disease, amyloid-β , behavior test, chloride, retina

DOI: 10.3233/ADR-230051

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1187-1200, 2023

Authors: Ibrahim, Yehia | Xie, Jianyang | Macerollo, Antonella | Sardone, Rodolfo | Shen, Yaochun | Romano, Vito | Zheng, Yalin

Article Type: Systematic Review

Abstract: Background: Traditional methods for diagnosing dementia are costly, time-consuming, and somewhat invasive. Since the retina shares significant anatomical similarities with the brain, retinal abnormalities detected via optical coherence tomography (OCT) and OCT angiography (OCTA) have been studied as a potential non-invasive diagnostic tool for neurodegenerative disorders; however, the most effective retinal changes remain a mystery to be unraveled in this review. Objective: This study aims to explore the relationship between retinal abnormalities in OCT/OCTA images and cognitive decline as well as evaluating biomarkers’ effectiveness in detecting neurodegenerative diseases. Methods: A systematic search was conducted on PubMed, …Web of Science, and Scopus until December 2022, resulted in 64 papers using agreed search keywords, and inclusion/exclusion criteria. Results: The superior peripapillary retinal nerve fiber layer (pRNFL) is a trustworthy biomarker to identify most Alzheimer’s disease (AD) cases; however, it is inefficient when dealing with mild AD and mild cognitive impairment (MCI). The global pRNFL (pRNFL-G) is another reliable biomarker to discriminate frontotemporal dementia from mild AD and healthy controls (HCs), moderate AD and MCI from HCs, as well as identifing pathological Aβ42 /tau in cognitively healthy individuals. Conversely, pRNFL-G fails to realize mild AD and the progression of AD. The average pRNFL thickness variation is considered a viable biomarker to monitor the progression of AD. Finally, the superior and average pRNFL thicknesses are considered consistent for advanced AD but not for early/mild AD. Conclusions: Retinal changes may indicate dementia, but further research is needed to confirm the most effective biomarkers for early and mild AD. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, neurodegenerative disorders, optical coherence tomography, optical coherence tomography angiography, retinal biomarkers

DOI: 10.3233/ADR-230042

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1201-1235, 2023

Authors: Vassilaki, Maria | Syrjanen, Jeremy A. | Krell-Roesch, Janina | Graff-Radford, Jonathan | Vemuri, Prashanthi | Scharf, Eugene L. | Machulda, Mary M. | Fields, Julie A. | Kremers, Walter K. | Lowe, Val J. | Jack Jr., Clifford R. | Knopman, David S. | Petersen, Ronald C. | Geda, Yonas E.

Article Type: Short Communication

Abstract: The study included 1,738 Mayo Clinic Study of Aging participants (≥50 years old; 1,460 cognitively unimpaired and 278 with mild cognitive impairment (MCI)) and examined the cross-sectional association between cerebrovascular (CVD) imaging biomarkers (e.g., white matter hyperintensities (WMH), infarctions) and Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) scores, as well as their association with MCI. High (abnormal) WMH burden was significantly associated with having BDI-II>13 and BAI > 7 scores, and both (CVD imaging biomarkers and depression/anxiety) were significantly associated with MCI when included simultaneously in the model, suggesting that both were independently associated with the odds of MCI.

Keywords: Alzheimer’s disease, anxiety, cerebrovascular, depression, mild cognitive impairment, neuroimaging

DOI: 10.3233/ADR-230073

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1237-1246, 2023

Authors: Ding, Yanfei | Chen, Haijuan | Yan, Yi | Qiu, Yinghui | Zhao, Aonan | Li, Binyin | Xu, Wei | Deng, Yulei

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multi-gene inherited disease, and apolipoprotein E (APOE ) ɛ4 is a strong risk factor. Other genetic factors are important but limited. Objective: This study aimed to investigate the relationship between 17 single-nucleotide polymorphisms (SNPs) and AD in the Southern Chinese populations. Methods: We recruited 242 AD patients and 208 controls. The SNaPshot technique was used to detect the SNPs. Results: Adjusted for sex and age, we found rs6572869 (FERMT2 ), rs11604680 (CELF1 ), and rs1317149 (CELF1 ) were associated with AD risk in the dominant (rs6572869: p  = 0.022, …OR = 1.55; rs11604680: p  = 0.007, OR = 1.68; rs1317149: p  = 0.033, OR = 1.50) and overdominant models (rs6572869: p  = 0.001, OR = 1.96; rs11604680: p  = 0.002, OR = 1.82; rs1317149: p  = 0.003, OR = 1.80). rs9898218 (COPI ) was associated with AD risk in the overdominant model (p  = 0.004, OR = 1.81). Further, rs2741342 (CHRNA2 ) was associated with AD protection in the dominant (p  = 0.002, OR = 0.5) and additive models (p  = 0.002, OR = 0.64). Mutations in rs10742814 (CELF1 ), rs11039280 (CELF1 ), and rs3752242 (ABCA7 ) contributed to AD protection. Among them, rs10742814 (CELF1 ), rs3752242 (ABCA7 ), and rs11039280 (CELF1 ) were more significantly associated with AD carrying APOE ɛ4, whereas rs1317149 (CELF1 ) showed an opposite trend. Interestingly, rs4147912 (ABCA7 ) and rs2516049 (HLA-DRB1 ) were identified to be relevant with AD carrying APOE ɛ4. Using expression quantitative trait locus analysis, we found polymorphisms in CELF1 (rs10742814 and rs11039280), ABCA7 (rs4147912), HLA-DRB1 (rs2516049), and ADGRF4 (rs1109581) correlated with their corresponding gene expression in the brain. Conclusions: We identified four risk and four protective SNPs associated with AD in the Southern Chinese population, with different correlations between APOE ɛ4 carriers and non-carriers. rs4147912 (ABCA7 ) and rs2516049 (HLA-DRB1 ) were associated with AD carrying APOE ɛ4. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, neurodegenerative disease, single nucleotide polymorphisms

DOI: 10.3233/ADR-230072

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1247-1257, 2023

Authors: Domene-Serrano, Indalo | Cuadros, Raquel | Hernandez, Felix | Avila, Jesus | Santa-Maria, Ismael

Article Type: Research Article

Abstract: Background: Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Recently, we have discovered a new, human specific, tau isoform termed W-tau that originates by intron 12 retention. Our preliminary data suggests this newly discovered W-tau isoform might prevent aberrant aggregation of other tau isoforms but is significantly downregulated in tauopathies such as Alzheimer's disease. Objective: To accurately predict, examine, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Methods: A tridimensional deep learning-based approach and in vitro polymerization assay was included to accurately predict, analyze, …and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Results: Our findings demonstrate: a) the predicted protein tridimensionality structure of the tau isoforms raised by intron retention and their comparison with the other tau isoforms; b) the interaction of W-tau peptide (from W-tau isoform) with other tau isoforms; c) the effect of W-tau peptide in the polymerization of those tau isoforms. Conclusions: This study supports the importance of the structure-function relationship on the neuroprotective behavior of W-tau inhibiting tau fibrillization in vitro . Show more

Keywords: Alzheimer’s disease, deep learning, intron retention, isoform, polymerization, splicing, tau protein, tridimensional structure

DOI: 10.3233/ADR-230074

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1259-1265, 2023

Authors: Chen, Yuanyuan | Lan, Meijuan

Article Type: Other

Abstract: Background: One of the most popular ways to address cognitive decline is cognitive training. The fact that cognitive deterioration is permanent is one of the main issues. This issue might be resolved by preventive cognitive training when it is acute. As a result, this study aims to design and assess how well stroke patients respond to hierarchical, multi-dimensional preventative cognitive training. Objective: To describe the study design of this center implementation trial. Methods: Participants in the study will be recruited from a hospital in China and randomly assigned to the intervention group or the usual care …group. Interventions will include four-week hierarchical multi-dimensional preventive cognitive training through a WeChat program. for Primary outcome measures will be the Montreal Cognitive Assessment, Mini-Mental State Examination, and Post-Stroke Cognitive Impairment (PSCI) Incidence. The secondary outcome measure will include the Hamilton Depression Scale, Hamilton Anxiety Scale, Modified Barthel Index, and National Institutes of Health Neurological Deficit Score. Outcomes will be measured at baseline, 12 weeks, and 24 weeks from the baseline. Results: We expect that the hierarchical multi-dimensional preventive cognitive training program will be easy to implement, and the cognitive function, cognitive psychology, ability of daily living will vary in each setting. Conclusions: The results will provide evidence highlighting differences in a new strategy of cognitive training through the WeChat program, which allows the home-based practice, puts forward an advanced idea of preventive cognitive training in the acute stage, and has the highest effectiveness of reducing cognitive impairment, and Alzheimer’s disease. Show more

Keywords: Acute stage, Alzheimer’s disease, cognitive training, post-stroke cognitive impairment, preventive

DOI: 10.3233/ADR-230097

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1267-1275, 2023

Authors: Gharbi, Alya | Nasri, Amina | Sghaier, Ikram | Kacem, Imen | Mrabet, Saloua | Souissi, Amira | Ben Djebara, Mouna | Gargouri, Amina | Gouider, Riadh

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disease with various clinical symptoms. Limited data have described the clinical subtypes of DLB. Objective: We aimed to compare clinical subtypes of DLB according to initial symptoms and to study the effect of Apolipoprotein E (APOE ) gene in DLB. Methods: We included DLB patients classified into three groups based on initial symptoms: non-motor onset (cognitive and/or psychiatric) (NMO-DLB), motor onset (parkinsonism and/or gait disorders) (MO-DLB), and mixed onset (non-motor and motor symptoms) (MXO-DLB). Clinical and APOE genotype associations and survival were analyzed. …Results: A total of 268 patients were included (NMO-DLB = 75%, MXO-DLB = 15.3%, MO-DLB = 9.7%). Visual hallucinations were more frequent (p = 0.025), and attention was less commonly impaired in MXO-DLB (p = 0.047). When adjusting with APOE ɛ 4 status (APOE genotype performed in 155 patients), earlier falls and frontal lobe syndrome were more common in MXO-DLB (p = 0.044 and p = 0.023, respectively). The median MMSE decline was 2.1 points/year and the median FAB decline was 1.9 points/year, with no effect of clinical subtypes. Median survival was 6 years. It was similar in DLB subtypes (p = 0.62), but shorter for patients with memory symptoms at onset (p = 0.04) and for males (p = 0.0058). Conclusions: Our study revealed a few differences between DLB clinical subtypes. APOE ɛ 4 appears to be associated with earlier falls and a higher prevalence of frontal syndrome in MXO-DLB. However, DLB clinical subtypes did not impact on survival. Nevertheless, survival analysis identified other poor prognosis factors, notably inaugural memory impairment and male gender. Show more

Keywords: Alzheimer’s disease, dementia, genetic, Lewy bodies, survival

DOI: 10.3233/ADR-230064

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1277-1288, 2023

Authors: Zhu, Haohao | Lu, Rongrong | Zhou, Qin | Du, Zhiqiang | Jiang, Ying

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder whose etiology involves multiple genetic and environmental factors. Sphingomyelin (SM) is a type of sphingolipid found in cell membranes, and recent evidence suggests a potential link between SM and AD. However, the nature of this relationship remains unclear. Objective: To elucidate the potential causal relationship between SM levels and the risk of developing AD using a two-sample Mendelian randomization approach. Methods: The study utilized data extracted from the genome wide association study database. The primary analysis method was the inverse variance weighted (IVW) method, which was supplemented …by weighted median, weighted mode, and MR Egger methods. The study specifically investigated the bidirectional causal relationship between SM and AD, evaluating odds ratios (OR) with a 95% confidence interval (95% CI). Results: Elevated levels of SM were found to be a risk factor for AD, as shown by IVW(MRE) [OR: 1.001, 95% CI: 1.000 to 1.002; p  = 0.020 < 0.05], IVW(FE) [OR: 1.001, 95% CI: 1.001 to 1.002; p  = 3.36e-07 < 0.05], and MR Egger. Conversely, AD was demonstrated to lead to an increase in SM levels [IVW(MRE): OR: 5.64e+08, 95% CI: 1.69e+05 to 1.89e+12; p  = 1.14e-06 < 0.05], with consistent findings across the IVW(FE), MR Egger, weighted median, and weighted mode methods. Conclusions: The study establishes a bidirectional positive correlation between SM and AD. Increased SM levels are associated with a higher risk of developing AD, and the presence of AD can further elevate SM levels, potentially exacerbating the disease’s progression. Show more

Keywords: Alzheimer’s disease, bidirectional Mendelian randomization, genome-wide association study, relationship, sphingomyelin

DOI: 10.3233/ADR-230126

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1289-1297, 2023

Authors: van Gils, Veerle | Ramakers, Inez | Jansen, Willemijn J. | Banning, Leonie | Kučikienė, Domantė | Costa, Ana Sofia | Schulz, Jörg B. | Visser, Pieter Jelle | Verhey, Frans | Reetz, Kathrin | Vos, Stephanie J.B.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline. Objective: To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population. Methods: We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aβ42 using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive …functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions. Results: At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ – 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions. Conclusions: Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cardiovascular risk, cognitive decline, magnetic resonance imaging, vascular diseases

DOI: 10.3233/ADR-230040

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1299-1311, 2023

Authors: Feldner, Alyssa C. | Turner, Andrew K. | Simpson, James F. | Estus, Steven

Article Type: Research Article

Abstract: Background: Understanding the mechanisms whereby genetic variants influence the risk of Alzheimer’s disease (AD) may provide insights into treatments that could reduce AD risk. Objective: Here, we sought to test the hypothesis that a single nucleotide polymorphism (SNP) associated with AD risk, rs2070902, influences splicing of FCER1G exon 2. Methods: AD and non-AD brain samples were analyzed for FCER1G expression by genotyping, immunohistochemistry, immunofluorescence, and qPCR. Results: The protein encoded by FCER1G, FcRγ , is robustly expressed in microglia in both AD and non-AD brain. The FCER1G isoform lacking exon …2 (D2-FCER1G ) was readily detectable. Moreover, the proportion of FCER1G expressed as this isoform was increased in brains with high AD neuropathology. However, the proportion of FCER1G expressed as the D2-FCER1G isoform was not associated with rs2070902 genotype. Conclusions: In summary, the proportion of FCER1G expressed as the D2-FCER1G isoform is increased with AD neuropathology but is not associated with rs2070902. Show more

Keywords: Alzheimer’s disease, genetics, microglia, polymorphism, RNA splicing

DOI: 10.3233/ADR-230076

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1313-1322, 2023

Authors: Mudalige, Dinithi | Guan, Dylan X. | Ghahremani, Maryam | Ismail, Zahinoor

Article Type: Research Article

Abstract: Background: Clinical guidelines recommend incorporating non-cognitive markers like mild behavioral impairment (MBI) and sleep disturbance (SD) into dementia screening to improve detection. Objective: We investigated the longitudinal associations between MBI, SD, and incident dementia. Methods: Participant data were from the National Alzheimer’s Coordinating Center in the United States. MBI was derived from the Neuropsychiatric Inventory Questionnaire (NPI-Q) using a published algorithm. SD was determined using the NPI-Q nighttime behaviors item. Cox proportional hazard regressions with time-dependant variables for MBI, SD, and cognitive diagnosis were used to model associations between baseline 1) MBI and incident SD (n … = 11,277); 2) SD and incident MBI (n  = 10,535); 3) MBI with concurrent SD and incident dementia (n  = 13,544); and 4) MBI without concurrent SD and incident dementia (n  = 11,921). Models were adjusted for first-visit age, sex, education, cognitive diagnosis, race, and for multiple comparisons using the Benjamini-Hochberg method. Results: The rate of developing SD was 3.1-fold higher in older adults with MBI at baseline compared to those without MBI (95% CI: 2.8–3.3). The rate of developing MBI was 1.5-fold higher in older adults with baseline SD than those without SD (95% CI: 1.3–1.8). The rate of developing dementia was 2.2-fold greater in older adults with both MBI and SD, as opposed to SD alone (95% CI:1.9–2.6). Conclusions: There is a bidirectional relationship between MBI and SD. Older adults with SD develop dementia at higher rates when co-occurring with MBI. Future studies should explore the mechanisms underlying these relationships, and dementia screening may be improved by assessing for both MBI and SD. Show more

Keywords: Alzheimer’s disease, dementia, longitudinal studies, neurobehavioral manifestations, sleep disorders

DOI: 10.3233/ADR-230086

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1323-1334, 2023

Authors: Zainuddin, Muhammad-Safuan | Bhuvanendran, Saatheeyavaane | Radhakrishnan, Ammu K. | Azman, Adzzie-Shazleen

Article Type: Review Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized as rapid and progressive cognitive decline affecting 26 million people worldwide. Although immunotherapies are ideal, its clinical safety and effectiveness are controversial, hence, treatments are still reliant on symptomatic medications. Concurrently, the Streptomyces genus has attracted attention given its pharmaceutically beneficial secondary metabolites to treat neurodegenerative diseases. Objective: To present secondary metabolites from Streptomyces sp. with regulatory effects on proteins and identified prospective target proteins for AD treatment. Methods: Research articles published between 2010 and 2021 were collected from five databases and 83 …relevant research articles were identified. Post-screening, only 12 research articles on AD-related proteins were selected for further review. Bioinformatics analyses were performed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network, PANTHER Go-Slim classification system (PANTHER17.0), and Kyoto Encyclopedia of Genes and Genomes (KEGG) Mapper. Results: A total of 20 target proteins were identified from the 12 shortlisted articles. Amyloid-β, BACE1, Nrf-2, Beclin-1, and ATG5 were identified as the potential target proteins, given their role in initiating AD, mitigating neuroinflammation, and autophagy. Besides, 10 compounds from Streptomyces sp., including rapamycin, alborixin, enterocin, bonnevillamides D and E, caniferolide A, anhydroexfoliamycin, rhizolutin, streptocyclinone A and B, were identified to exhibit considerable regulatory effects on these target proteins. Conclusions: The review highlights several prospective target proteins that can be regulated through treatments with Streptomyces sp. compounds to prevent AD’s early stages and progression. Further identification of Streptomyces sp. compounds with potential anti-AD properties is recommended. Show more

Keywords: Alzheimer’s disease, amyloid-β , secondary metabolites, Streptomyces sp

DOI: 10.3233/ADR-230065

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1335-1350, 2023

Authors: Zhang, Hongwei | Liu, Da | Duan, Yuanyuan | Liu, Yan | Liu, Jianyu | Bai, Na | Zhou, Qiang | Xu, Zhiyao | Li, Linyan | Liu, Hua

Article Type: Systematic Review

Abstract: Background: The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer’s disease (AD) has been widely studied across populations; however, the results are inconsistent. Objective: This study aimed to evaluate the association of A2M gene with AD by the application of meta-analysis. Methods: Relevant studies were identified by comprehensive searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratio (OR) with corresponding 95% confidence intervals (CI) was calculated using a random-effects or fixed-effects model. The Cochran Q statistic and I2 …metric was used to evaluate heterogeneity, and Egger’s test and Funnel plot were used to assess publication bias. Results: A total of 62 studies were identified and included in the current meta-analysis. The G allele of rs226380 reduced AD risk (OR: 0.64, 95% CI: 0.47–0.87, pFDR = 0.012), but carrier with the TT genotype was more likely to develop AD in Asian populations (OR: 1.56, 95% CI: 1.12–2.19, pFDR = 0.0135). The V allele of the A2M-I/V (rs669) increased susceptibility to AD in female population (OR, 95% CI: 2.15, 1.38–3.35, pFDR = 0.0024); however, the II genotype could be a protective factor in these populations (OR, 95% CI: 0.43, 0.26–0.73, pFDR = 0.003). Sensitivity analyses confirmed the reliability of the original results. Conclusions: Existing evidence indicate that A2M single nucleotide polymorphisms (SNPs) may be associated with AD risk in sub-populations. Future studies with larger sample sizes will be necessary to confirm the results. Show more

Keywords: Alpha 2-macroglobulin, Alzheimer’s disease, A2M, meta-analysis, SNPs, systematic review

DOI: 10.3233/ADR-230131

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1351-1370, 2023

Authors: Tsapanou, Angeliki | Zoi, Panagiota | Kalligerou, Faidra | Blekou, Patra | Sakka, Paraskevi

Article Type: Short Communication

Abstract: What is the impact of long COVID-19 on people with mild cognitive impairment (MCI) or dementia? Self-reported questionnaire was used for the report of long COVID-19 symptoms. People with MCI or dementia or their caregivers regarding patients’ health were recruited COVID-19 throughout from the Athens Alzheimer’s Association. We included 72 participants. Thirty had the diagnosis of MCI and 39 had dementia. Most symptoms lasted for 3-4 weeks. The majority of patients reported having all the symptoms, with fatigue being the major disturbance. The diagnosis and the management of long COVID-19 symptoms requires a more holistic and comprehensive approach.

Keywords: Alzheimer’s disease, COVID-19, dementia, long COVID, mild cognitive impairment

DOI: 10.3233/ADR-230119

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1371-1375, 2023

Authors: Tsatali, Marianna | Angelidou, Ioanna Antigoni | Tsolaki, Magda | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: Measuring dementia knowledge can be a valuable tool for assessing the effectiveness of dementia awareness activities, identifying the potential benefits of dementia training programs, and breaking down common myths and stereotypes about dementia. Objective: To compare the psychometric properties of three widely used dementia knowledge tools, the Dementia Knowledge Assessment Tool 2 (DKAT2-G), the Dementia Knowledge Assessment Scale (DKAS-G), and the Knowledge in Dementia Scale (KIDE-G) in the Greek adult population. Methods: A convenience sample of 252 participants from the general population completed the survey online. Statistical analyses included Cronbach’s internal reliability, retest reliability, factor …analysis, concurrent and construct validity, and floor and ceiling effects. Results: The DKAS-G had the most appropriate reliability levels (Cronbach’s alpha  =  0.845; retest reliability  =  0.921), whereas the DKAT2-G had satisfactory indexes (Cronbach’s α = 0.760; retest reliability  =  0.630). The KIDE-G showed unsatisfactory reliability (Cronbach’s α = 0.419; retest reliability  =  0.619). Construct validity was confirmed for all questionnaires, showing that all of them detected participants with pre-existing knowledge of dementia. Confirmatory factor analysis revealed a four-factor model for the DKAS-G and proposed the removal of 5 items. Floor and ceiling effects were found for the DKAT2-G and the KIDE-G, mainly among those who had previously participated in dementia training. Conclusions: The DKAS-G was found to have the highest levels of reliability and validity. The results prove that the DKAS-G meets the requirements for measuring dementia knowledge and evaluating dementia training programs in health professionals, caregivers, and the general population. Show more

Keywords: Alzheimer’s disease, knowledge, reliability and validity, test-retest reliability, validation study

DOI: 10.3233/ADR-230161

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1377-1393, 2023

Authors: André, Séverine | Verteneuil, Sébastien | Ris, Laurence | Kahvecioglu, Zehra-Cagla | Nonclercq, Denis | De Winter, Julien | Vander Elst, Luce | Laurent, Sophie | Muller, Robert N. | Burtea, Carmen

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA2 -IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach. Objective: A cPLA2 -IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy. Methods: We targeted the cPLA2 -IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic …acid dosage [AA], cPLA2 -IVA cellular translocation) before being tested in vivo . We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA2 -IVA itself, the NMDA receptor, AβPP and tau by IHC after i.v. injection in APP/PS1 mice. Results: Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA2 -IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA2 -IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation. Conclusions: cPLA2 -IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, amyloid plaques, cytosolic phospholipase A2, peptides, phage display, tau protein

DOI: 10.3233/ADR-230075

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1395-1426, 2023

Authors: Goodman, Max J. | Li, Xin Ran | Livschitz, Jennifer | Huang, Chiang-Ching | Bendlin, Barbara B. | Granadillo, Elias D.

Article Type: Research Article

Abstract: Background: Physicians may soon be able to diagnose Alzheimer’s disease (AD) in its early stages using fluid biomarkers like amyloid. However, it is acknowledged that additional biomarkers need to be characterized which would facilitate earlier monitoring of AD pathogenesis. Objective: To determine if a potential novel inflammation biomarker for AD, symmetric dimethylarginine, has utility as a baseline serum biomarker for discriminating prodromal AD from cognitively unimpaired controls in comparison to cerebrospinal fluid amyloid-β42 (Aβ42 ). Methods: Data including demographics, magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography scans, Mini-Mental State Examination and Functional Activities Questionnaire scores, and …biomarker concentrations were obtained from the Alzheimer’s Disease Neuroimaging Initiative for a total of 146 prodromal AD participants and 108 cognitively unimpaired controls. Results: Aβ42 (p  = 0.65) and symmetric dimethylarginine (p  = 0.45) were unable to predict age-matched cognitively unimpaired controls and prodromal AD participants. Aβ42 was negatively associated with regional brain atrophy and hypometabolism as well as cognitive and functional decline in cognitively unimpaired control participants (p  < 0.05) that generally decreased in time. There were no significant associations between Aβ42 and symmetric dimethylarginine with imaging or neurocognitive biomarkers in prodromal AD patients. Conclusions: Correlations were smaller between Aβ42 and neuropathological biomarkers over time and were absent in prodromal AD participants, suggesting a plateau effect dependent on age and disease stage. Evidence supporting symmetric dimethylarginine as a novel biomarker for AD as a single measurement was not found. Show more

Keywords: Alzheimer’s disease, amyloid, biomarker, methylarginines, SDMA, serum markers

DOI: 10.3233/ADR-230054

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1427-1444, 2023

Authors: Balietti, Marta | Galeazzi, Roberta | Giacconi, Robertina | Santillo, Elpidio | Giuli, Cinzia

Article Type: Research Article

Abstract: Background: Elevated cortisol levels represent a risk factor for Alzheimer’s disease (AD), prompting treatments to lower hormone concentrations for preventive or therapeutic purposes. Objective: To assess the efficacy of a comprehensive intervention (CI) in modulating serum cortisol levels in patients with AD. Methods: CI consisted in a 2-month protocol involving cognitive stimulation, psychological support, lifestyle guidance, leisure activities, and socialization. AD subjects were randomly assigned to experimental (EG, n  = 45) and control (CG, n  = 45) groups. A wide range of sociodemographic, cognitive, psychosocial, and functional conditions were evaluated before, at the conclusion, and 24 months after …CI. Data about lifestyle and drug prescription were also recorded. Results: Baseline evaluations revealed that higher cortisol levels correlated with worse cognitive status (higher CDR and ADAS-Cog values and lower MMSE scores), increased depressive symptoms, and reduced physical and social engagement. Following CI, EG exhibited reduced cortisol levels, improved overall cognitive status, and enhanced verbal working memory and executive functions compared to CG. However, at the 24-month follow-up, EG displayed a rebound effect, characterized by elevated cortisol levels and cognitive decline compared to CG. Conclusions: These findings strengthen the adverse relationship between excessive cortisol and deficits in cognition/behavior in AD, demonstrate the short-term benefits of CI, and emphasize the potential long-term risks, which may be attributed to the fragile nature of the AD brain. Comprehensive interventions can yield positive results, but careful calibration of type and duration is necessary, considering disease progression and the potential need for re-administration. Show more

Keywords: Alzheimer’s disease, cognitive performance, comprehensive intervention, cortisol

DOI: 10.3233/ADR-230125

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1445-1453, 2023

Authors: Bonilla-Santos, Jasmin | González-Hernández, Alfredis | Cala-Martínez, Dorian Yisela | Gómez-Morales, Duván Fernando | Calceto-Garavito, Laura Natalia | Forero-Aldana, Arnulfo Eduardo | González-Montealegre, Rodrigo Alberto | Cardona Cumaco, Yeing Alexandra | Rojas-Bernal, Luz Angela | Zabaleta-Orozco, Mario Alberto | Parra, Mario Alfredo

Article Type: Research Article

Abstract: Background: Recent reports suggest that by 2050 there will be an increase of around 310% of cases affected by dementia in Latin American countries. A previous study in a Southern region reported one of the highest prevalences of dementia in Latin America. Objective: To investigate the prevalence of mild cognitive impairment associated with low education, rurality, and demographic characteristics. Methods: A cross-sectional study recruited a community-dwelling sample of 823 adults from rural and urban areas of two Southern provinces of Colombia from 2020–2022. Participants were assessed with a neuropsychological protocol validated in Colombia. To obtain general …and region-specific prevalence rates, age, sex, schooling, and socioeconomic level were considered and controlled for. Results: Most of the participants reported low education and socioeconomic level, the participation of women was higher. It was determined that the prevalence of mild cognitive impairment (MCI) was 53.6%, with 56.6% in the province of Caquetá followed by 51.9% in the province of Huila. The amnestic MCI represented 42.6%, the amnestic multi-domain was 39%, the non-amnestic 16.55%, and the non-amnestic multi-domain 1.81%. Our participants reported comorbidities such as diabetes and hypertension. We also observed a relationship between exposure to pesticides and MCI. Conclusions: We observed one of the highest prevalences of MCI in Latin America reported to date. Variables such as age, gender, and education proved risk factors for MCI in the explored regions. Our findings are very much in line with recent studies that highlight the influence of non-canonical risk factors of dementia in underrepresented countries from Latin America. Show more

Keywords: Alzheimer’s disease, epidemiology, mild cognitive impairment, pesticides, prevalence

DOI: 10.3233/ADR-230041

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1455-1464, 2023

Authors: Han, Sang-Won | Lee, Sang-Hwa | Kim, Jong Ho | Lee, Jae-Jun | Park, Young Ho | Kim, SangYun | Nho, Kwangsik | Sohn, Jong-Hee

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles in the brain. Emerging evidence has suggested potential interactions between the brain and periphery, particularly the liver, in regulating Aβ homeostasis. Objective: This study aimed to investigate the association of serum liver enzymes with brain amyloidopathy and cognitive performance in patients with complaints of cognitive decline. Methods: A total of 1,036 patients (mean age 74 years, 66.2% female) with subjective cognitive decline, mild cognitive impairment, AD dementia, and other neurodegenerative diseases were included using the Smart Clinical Data Warehouse. Amyloid positron emission …tomography (PET) imaging, comprehensive neuropsychological evaluations, and measurements of liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, and albumin, were assessed. After propensity score matching, logistic and linear regression analyses were used to investigate the associations between liver enzymes, amyloid status, and cognitive performance. Additionally, a machine learning approach was used to assess the classification performance of liver enzymes in predicting amyloid PET positivity. Results: Lower ALT levels and higher AST-to-ALT ratios were significantly associated with amyloid PET positivity and AD diagnosis. The AST-to-ALT ratio was also significantly associated with poor memory function. Machine learning analysis revealed that the classification performance of amyloid status (AUC = 0.642) for age, sex, and apolipoprotein E ɛ 4 carrier status significantly improved by 6.2% by integrating the AST-to-ALT ratio. Conclusions: These findings highlight the potential association of liver function on AD and its potential as a diagnostic and therapeutic implications. Show more

Keywords: Alzheimer’s disease, amyloid PET, cognition, liver enzymes, machine learning

DOI: 10.3233/ADR-230148

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1465-1474, 2023

Authors: Baldimtsi, Eleni | Mouzakidis, Christos | Karathanasi, Eleni Maria | Verykouki, Eleni | Hassandra, Mary | Galanis, Evangelos | Hatzigeorgiadis, Antonis | Goudas, Marios | Zikas, Paul | Evangelou, Giannis | Papagiannakis, George | Bellis, George | Kokkotis, Christos | Tsatalas, Themistoklis | Giakas, Giannis | Theodorakis, Yannis | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Virtual reality (VR) technology has become increasingly used for assessment and intervention in the neuroscience field. Objective: We aimed to investigate the effects of a VR Training System, named VRADA (VR Exercise App for Dementia and Alzheimer’s Patients), on the cognitive functioning of older people with mild cognitive impairment (MCI). Methods: In this intervention study, 122 older adults with MCI were randomly assigned to five groups (the VRADA group (n  = 28), a bike group (n  = 11), a physical exercise group (n  = 24), a mixed group (physical and cognitive exercise) (n  = 31), and a non-contact control …group (n  = 28). The VRADA group underwent 32 physical and cognitive training sessions, performed 2 or 3 times weekly for 12 weeks in the VR environment. All participants had detailed neuropsychological assessments before and after intervention. Results: A series of linear regression models revealed that the VRADA group showed improvement or no deterioration in cognitive decline in global cognitive function (MMSE), verbal memory (Rey Auditory Verbal Learning Test and WAIS forward test), and executive functions, mental flexibility (Trail Making Test B). Conclusions: This interventionstudy indicates that the VRADA system improves the cognitive function of elders with MCI. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, multi-component intervention, physical-cognitive training, virtual reality

DOI: 10.3233/ADR-230099

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1475-1490, 2023