Journal of Alzheimer's Disease - Volume 97, issue 2

Authors: Nguyen, Sarah A. | Oughli, Hanadi Ajam | Lavretsky, Helen

Article Type: Review Article

Abstract: Integrative medicine takes a holistic approach because it considers multiple aspects of the individual. This includes a person’s physical, emotional, interpersonal, behavioral, nutritional, environmental, and spiritual dimensions of wellbeing that contribute to the Whole Person Health. There is increasing interest and popularity of integrative approaches to treating cognitive decline and dementia because of the multifactorial nature of aging and the limited pharmacological interventions available in treating cognitive decline and dementia, particularly Alzheimer’s disease, the most common type of dementia. This review summarizes the existing evidence using complementary and integrative medicine therapies in cognitive decline and Alzheimer’s disease. This includes the …use of mind-body therapies, lifestyle interventions (nutritional, physical exercise, stress reduction), and other integrative modalities. Unfortunately, there are still limited studies available to guide clinicians despite the increasing popularity of integrative treatments. Show more

Keywords: Alternative, Alzheimer’s disease, complementary, dementia, integrative, neurocognitive disorders

DOI: 10.3233/JAD-230710

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 523-540, 2024

Authors: Toh, Keith Z.X. | Koh, Ming Yi | Loh, Enver D.W. | Sia, Ching-Hui | Chong, Yaofeng | Yeo, Leonard L.L. | Sharma, Vijay K. | Lim, Mervyn J.R. | Tan, Benjamin Y.Q.

Article Type: Systematic Review

Abstract: Background: Cognitive impairment, and in the long term Alzheimer’s disease, vascular, or mixed dementia, are potential complications of moyamoya disease (MMD), of which the prevalence and associations are not well established. Objective: We performed a systematic review and meta-analysis to investigate the prevalence of cognitive impairment in adult patients with MMD as well as its clinical and demographic correlates. Methods: We performed a systematic search of four electronic databases: PubMed (MEDLINE), EMBASE, Scopus, and Cochrane Library, profiling studies from inception until 7 May 2023. Clinical data consisting of population characteristics, comorbidities, cognitive assessment tools used, and …prevalence of cognitive impairment was extracted. Results: Seventeen studies were included in the meta-analysis, with a total study population of 1,190 patients. All studies assessed cognition, and the overall prevalence of cognitive impairment in MMD patients was 54.59%. A subgroup analysis identified that the prevalence of executive dysfunction in MMD patients was 31.55%. We performed a meta-regression analysis which identified that cognitive impairment was not associated with age, education level, or a history of ischemic or hemorrhagic stroke. Conclusions: A substantial proportion of MMD patients have cognitive impairment, and cognitive impairment was found to have no association with a history of stroke. Further research is necessary to investigate the longitudinal relationship of MMD and cognitive impairment, and the impact of bypass surgery on cognitive impairment. Show more

Keywords: Alzheimer’s disease, cognitive impairment, moyamoya disease, prevalence

DOI: 10.3233/JAD-230979

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 541-552, 2024

Authors: Keizer, Hiskias G. | Brands, Ruud | Oosting, Ronald S. | Seinen, Willem

Article Type: Research Article

Abstract: Despite decades of intense research, the precise etiology of Alzheimer’s disease (AD) remains unclear. In this hypothesis, we present a new perspective on this matter by identifying carnitine palmitoyl transferase-2 (CPT2) as a central target in AD. CPT2 is an enzyme situated within the inner mitochondrial membrane, playing a crucial role in beta-oxidation of fatty acids. It exhibits high sensitivity to hydrogen peroxide. This sensitivity holds relevance for the etiology of AD, as all major risk factors for the disease share a commonality in producing an excess of hydrogen peroxide right at this very mitochondrial membrane. We will explain the …high sensitivity of CPT2 to hydrogen peroxide and elucidate how the resulting inhibition of CPT2 can lead to the characteristic phenotype of AD, thus clarifying its central role in the disease’s etiology. This insight holds promise for the development of therapies for AD which can be implemented immediately. Show more

Keywords: Alzheimer’s disease, AMP-kinase pathway dependent integrated stress response, carnitine palmitoyl transferase 2, CPT2, hydrogen peroxide, hypoxia, longevity, radical oxygen species

DOI: 10.3233/JAD-230991

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 553-558, 2024

Authors: Dosso, Jill A. | Kailley, Jaya N. | Robillard, Julie M.

Article Type: Short Communication

Abstract: The quality of information about dementia retrieved using ChatGPT is unknown. Content was evaluated for length, readability, and quality using the QUEST, a validated tool, and compared against online material from three North American organizations. Both sources of information avoided conflicts of interest, supported the patient-physician relationship, and used a balanced tone. Official bodies but not ChatGPT referenced identifiable research and pointed to local resources. Users of ChatGPT are likely to encounter accurate but shallow information about dementia. Recommendations are made for information creators and providers who counsel patients around digital health practices.

Keywords: Alzheimer’s disease, artificial intelligence, dementia, health

DOI: 10.3233/JAD-230573

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 559-565, 2024

Authors: Digma, Leonardino A. | Winer, Joseph R. | Greicius, Michael D.

Article Type: Article Commentary

Abstract: With the FDA approval of aducanumab and lecanemab, and with the recent statistically significant phase 3 clinical trial for donanemab, there is growing enthusiasm for anti-amyloid antibodies in the treatment of Alzheimer’s disease. Here, we discuss three substantial limitations regarding recent anti-amyloid clinical trials: 1) there is little evidence that amyloid reduction correlates with clinical outcome, 2) the reported efficacy of anti-amyloid therapies may be explained by functional unblinding, and 3) donanemab had no effect on tau burden in its phase 3 trial. Taken together, these observations call into question the efficacy of anti-amyloid therapies.

Keywords: Alzheimer’s disease, amyloid, clinical trials, tau

DOI: 10.3233/JAD-231198

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 567-572, 2024

Authors: Maters, Jasper | van der Steen, Jenny T. | de Vugt, Marjolein E. | Bakker, Christian | Koopmans, Raymond T.C.M.

Article Type: Research Article

Abstract: Background: The evidence underpinning palliative care in dementia is mostly based on research in older populations. Little is known about the palliative care needs of people with young-onset dementia (YOD). Objective: To describe palliative care practices including advance care planning (ACP) in people with YOD residing in Dutch nursing homes. Methods: The study presents baseline questionnaire data from an observational cohort study. Physicians, family caregivers, and nursing staff completed questionnaires about 185 residents with YOD. The questionnaires included items on sociodemographics, quality of life measured with the quality of life in late-stage dementia (QUALID) scale, dementia-related …somatic health problems, symptoms, pain medication, psychotropic drugs, and ACP. Results: The mean age was 63.9 (SD 5.8) years. Half (50.3%) of them were female. Alzheimer’s disease dementia (42.2%) was the most prevalent subtype. The mean QUALID score was 24.0 (SD 7.9) as assessed by family caregivers, and 25.3 (SD 8.6) as assessed by the nursing staff. Swallowing problems were the most prevalent dementia-related health problem (11.4%). Agitation was often reported by physicians (42.0%) and nursing staff (40.5%). Psychotropics were prescribed frequently (72.3%). A minority had written advance directives (5.4%) or documentation on treatment preferences by the former general practitioner (27.2%). Global care goals most often focused on comfort (73.9%). Proportions of do-not-treat orders were higher than do-treat orders for all interventions except for hospitalization and antibiotics. Conclusions: ACP must be initiated earlier, before nursing home admission. A palliative approach seems appropriate even though residents are relatively young and experience few dementia-related health problems. Show more

Keywords: Advance care planning, Alzheimer’s disease, palliative care, young-onset dementia

DOI: 10.3233/JAD-230486

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 573-586, 2024

Authors: Almkvist, Ove | Larsson, Maria | Graff, Caroline

Article Type: Research Article

Abstract: Background: Impaired odor identification is a characteristic of sporadic Alzheimer’sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain. Objective: To investigate odor identification ability in mutation carriers (MC) and non-carriers (NC) of adAD in relation to years to estimated clinical onset clinical onset (YECO) of disease. Methods: Participants from six families with autosomal-dominant mutations (APP Swedish, APP Arctic, and PSEN1 mutations) included 20 MC and 20 NC. The groups were comparable in age, gender, education, number of APOE ɛ4 alleles, and YECO, but differed in global cognition (Mini-Mental State …Examination). The MC group included individuals in asymptomatic, symptomatic cognitively unimpaired, mild cognitive impairment, and dementia stages of disease, spanning approximately 40 years of the AD continuum. All NC were asymptomatic. Olfactory function was assessed by means of free and cued identification of common odors summarized as total identification. Results: MC performed poorer than NC in free and total identification. Four MC and none of the NC were anosmic. Olfactory functions in MC and NC were significantly and inversely related to time course (YECO) for both free and total identification. The decline in free identification began approximately 10 years prior to the estimated clinical onset of AD in MC. Odor identification proficiency was associated with episodic memory and executive function in MC and NC. Conclusions: Impaired odor identification is present well before the clinical diagnosis of AD in MC and is associated with disease progression. Odor identification ability may be a useful early biomarker for adAD. Show more

Keywords: Alzheimer’s disease, autosomal-dominant Alzheimer’s disease, cognition, mutation carriers, non-carriers, odor identification

DOI: 10.3233/JAD-230618

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 587-598, 2024

Authors: Ricci, Francesco | Martorana, Alessandro | Bonomi, Chiara G. | Serafini, Chiara | Mercuri, Nicola B. | Koch, Giacomo | Motta, Caterina

Article Type: Research Article

Abstract: Background: Blood-brain barrier (BBB) dysfunction could favor the pathogenesis and progression of Alzheimer’s disease (AD). Vascular risk factors (VRF) could worsen BBB integrity, thus promoting neurode generation. Objective: To investigate BBB permeability and its relation with VRF along the AD continuum (ADc). Cerebrospinal fluid (CSF) Amyloid (A) and p-tau (T) levels were used to stratify patients. Methods: We compared CSF/plasma albumin ratio (QAlb) of 131 AD patients and 24 healthy controls (HC). APOE genotype and VRF were evaluated for each patient. Spearman’s Rho correlation was used to investigate the associations between Qalb …and CSF AD biomarkers. Multivariate regression analyses were conducted to explore the relationship between Qalb and AD biomarkers, sex, age, cognitive status, and VRF. Results: QAlb levels did not show significant difference between ADc patients and HC (p  = 0.984). However, QAlb was significantly higher in A  + T–compared to A  + T+ (p  = 0.021). In ADc, CSF p-tau demonstrated an inverse correlation with QAlb, a finding confirmed in APOE4 carriers (p  = 0.002), but not in APOE3 . Furthermore, in APOE4 carriers, sex, hypertension, and hypercholesterolemia were associated with QAlb (p  = 0.004, p  = 0.038, p  = 0.038, respectively), whereas only sex showed an association in APOE3 carriers (p  = 0.026). Conclusions: BBB integrity is preserved in ADc. Among AT categories, A  + T–have a more permeable BBB than A  + T+. In APOE4 carriers, CSF p-tau levels display an inverse association with BBB permeability, which in turn, seems to be affected by VRF. These data suggest a possible relationship between BBB efficiency, VRF and CSF p-tau levels depending on APOE genotype. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease continuum, APOE, biomarkers, blood-brain barrier, QAlb, vascular risk factors

DOI: 10.3233/JAD-230792

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 599-607, 2024

Authors: Ren, Jiawen | Yu, Yongquan | Wang, Yucheng | Dong, Yu | Shen, Xiaobing

Article Type: Research Article

Abstract: Background: Glyphosate is the most commonly used herbicide with potential neurotoxicity. However, limited epidemical evidence is found in the relationship between glyphosate and cognitive impairment, especially in the cognitive-disrupting sensitive elderly populations. Objective: This study aimed to examine the association of urinary glyphosate exposure with cognitive impairment in the United State (US) older adults. Methods: Cognitive impairment was determined by the following four tests: the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) Immediate Recall test (IR), the CERAD Delayed Recall tests (DR), the Animal Fluency (AF) test and the Digit Substitution test (DSST). Survey …weighted logistic regression and restricted cubic splines were applied to evaluate and visualize the association between glyphosate and cognitive impairment. Results: A total of 465 elderly adults were identified in the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle, and among them, 83.87% individuals had detectable urinary levels of glyphosate (0.628 ng/mL in average). After adjusting for the potential covariates, glyphosate was significantly linked to increased DR and AF impairment, and the corresponding ORs were 1.52 (1.01 to 2.30, p  = 0.049) and 1.69 (1.11 to 2.59, p  = 0.019), respectively. No significant association was identified between glyphosate and IR or DSST impairment. The RCS plot further confirmed the linear and positive relationships between glyphosate and DR and AF impairment. Conclusions: These findings suggested that exposure to glyphosate might be associated with declined cognitive function in the elderly, and it might be prudent to evaluate cognitive outcomes for aged individuals with glyphosate exposures. Show more

Keywords: Alzheimer’s disease, cognitive impairment, glyphosate, logistic regression, restricted cubic spline

DOI: 10.3233/JAD-230782

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 609-620, 2024

Authors: Rehman, Habbiburr | Ang, Ting Fang Alvin | Tao, Qiushan | Espenilla, Arielle Lauren | Au, Rhoda | Farrer, Lindsay A. | Zhang, Xiaoling | Qiu, Wei Qiao

Article Type: Research Article

Abstract: Background: Although cerebrospinal fluid (CSF) amyloid-β42 peptide (Aβ42 ) and phosphorylated tau (p-tau) and blood p-tau are valuable for differential diagnosis of Alzheimer’s disease (AD) from cognitively normal (CN) there is a lack of validated biomarkers for mild cognitive impairment (MCI). Objective: This study sought to determine how plasma and CSF protein markers compared in the characterization of MCI and AD status. Methods: This cohort study included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 75 proteins measured commonly in plasma and CSF (257 total, 46 CN, 143 MCI, and 68 AD). …Logistic regression, least absolute shrinkage and selection operator (LASSO) and Random Forest (RF) methods were used to identify the protein candidates for the disease classification. Results: We observed that six plasma proteins panel (APOE, AMBP, C3, IL16, IGFBP2, APOD) outperformed the seven CSF proteins panel (VEGFA, HGF, PRL, FABP3, FGF4, CD40, RETN) as well as AD markers (CSF p-tau and Aβ42 ) to distinguish the MCI from AD [area under the curve (AUC) = 0.75 (plasma proteins), AUC = 0.60 (CSF proteins) and AUC = 0.56 (CSF p-tau and Aβ42 )]. Also, these six plasma proteins performed better than the CSF proteins and were in line with CSF p-tau and Aβ42 in differentiating CN versus MCI subjects [AUC = 0.89 (plasma proteins), AUC = 0.85 (CSF proteins) and AUC = 0.89 (CSF p-tau and Aβ42 )]. These results were adjusted for age, sex, education, and APOE ϵ 4 genotype. Conclusions: This study suggests that the combination of 6 plasma proteins can serve as an effective marker for differentiating MCI from AD and CN. Show more

Keywords: Alzheimer’s disease, biomarkers, mild cognitive impairment, proteins

DOI: 10.3233/JAD-230837

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 621-633, 2024

Authors: Mahzarnia, Ali | Lutz, Michael W. | Badea, Alexandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) involves brain neuropathologies such as amyloid plaque and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand disease etiology and devise therapies. Objective: Our objective was to identify molecular pathways associated with hallmark AD biomarkers and cognitive status, accounting for variables such as age, sex, education, and APOE genotype. Methods: We introduce a pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of …the three phenotypes (amyloid-β, tau, cognition) using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved 634 subjects with data available for all three phenotypes, allowing for the identification of common pathways. Results: We identified 14 pathways significantly associated with amyloid-β; 5 associated with tau; and 174 associated with cognition, which showed a larger number of pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited associations with all three phenotypes. Mediation analysis showed that among the VEGF-RB family genes, ITGA5 mediates the relationship between cognitive scores and pathological biomarkers. Conclusions: We presented a new statistical approach linking continuous phenotypes, gene expression across pathways, and covariates like sex, age, and education. Our results reinforced VEGF RB2’s role in AD cognition and demonstrated ITGA5’s significant role in mediating the AD pathology-cognition connection. Show more

Keywords: Alzheimer’s disease, continuous GSLRT, likelihood ratio-derived test statistics, RNA-seq, VEGF

DOI: 10.3233/JAD-230934

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 635-648, 2024

Authors: Morgenstern, Lewis B. | Briceño, Emily M. | Mehdipanah, Roshanak | Chang, Wen | Lewandowski-Romps, Lisa | Gonzales, Xavier F. | Levine, Deborah A. | Langa, Kenneth M. | Garcia, Nelda | Khan, Noreen | Zahuranec, Darin B. | Heeringa, Steven G.

Article Type: Research Article

Abstract: Background: Little information is available on the prevalence of cognitive impairment in Mexican American persons. Objective: To determine the prevalence of mild cognitive impairment (MCI) and dementia in those 65 years and older among Mexican American and non-Hispanic white individuals in a community. Methods: This was a population-based cohort study in Nueces County, Texas, USA. Participants were recruited using a random housing sample. The Harmonized Cognitive Assessment (HCAP) participant and informant protocol was performed after Montreal Cognitive Assessment (MoCA) screening. An algorithm was used to sort participants into diagnostic categories: no cognitive impairment, …MCI, or dementia. Logistic regression determined the association of ethnicity with MCI and dementia controlling for age, gender, and education. Results: 1,901 participants completed the MoCA and 547 the HCAP. Mexican Americans were younger and had less educational attainment than non-Hispanic whites. Overall, dementia prevalence was 11.6% (95% CI 9.2–14.0) and MCI prevalence was 21.2% (95% CI 17.5–24.8). After adjusting for age, gender, and education level, there was no significant ethnic difference in the odds of dementia or MCI. Those with ≤11 compared with ≥16 years of education had much higher dementia [OR = 4.9 (95% CI 2.2–11.1)] and MCI risk [OR = 3.5 (95% CI 1.6–7.5)]. Conclusions: Dementia and MCI prevalence were high in both Mexican American and non-Hispanic white populations. Mexican American persons had double the odds of mild cognitive impairment and this was attenuated when age and educational attainment were considered. Educational attainment was a potent predictor of cognitive impairment. Show more

Keywords: Alzheimer’s disease, community, dementia, disparities, education, epidemiology, health equity, Hispanic, Mexican American, mild cognitive impairment

DOI: 10.3233/JAD-230729

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 649-658, 2024

Authors: Kosel, Filip | Hartley, Mackenzie Rae | Franklin, Tamara Brook

Article Type: Research Article

Abstract: Background: Neuroimaging studies investigating the behavioral and psychological symptoms of dementia (BPSD)— such as apathy, anxiety, and depression— have linked some of these symptoms with altered neural activity. However, inconsistencies in operational definitions and rating scales, limited scope of assessments, and poor temporal resolution of imaging techniques have hampered human studies. Many transgenic (Tg) mouse models of Alzheimer’s disease (AD) exhibit BPSD-like behaviors concomitant with AD-related neuropathology, allowing examination of how neural activity may relate to BPSD-like behaviors with high temporal and spatial resolution. Objective: To examine task-dependent neural activity in the medial prefrontal cortex (mPFC) of AD-model …mice in response to social and non-social olfactory stimuli. Methods: We previously demonstrated age-related decreases in social investigation in Tg 5xFAD females, and this reduced social investigation is evident in Tg 5xFAD females and males by 6 months of age. In the present study, we examine local field potential (LFP) in the mPFC of awake, behaving 5xFAD females and males at 6 months of age during exposure to social and non-social odor stimuli in a novel olfactometer. Results: Our results indicate that Tg 5xFAD mice exhibit aberrant baseline and task-dependent LFP activity in the mPFC— including higher relative delta (1–4 Hz) band power and lower relative power in higher bands, and overall stronger phase-amplitude coupling— compared to wild-type controls. Conclusions: These results are consistent with previous human and animal studies examining emotional processing, anxiety, fear behaviors, and stress responses, and suggest that Tg 5xFAD mice may exhibit altered arousal or anxiety. Show more

Keywords: Alzheimer’s disease, anxiety, arousal, behavioral and psychological symptoms of dementia, local field potentials, olfaction, phase-amplitude coupling, social odors, 5xFAD mice

DOI: 10.3233/JAD-230858

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 659-677, 2024

Authors: Park, Minah | Jang, Sung-In | Hurh, Kyungduk | Park, Eun-Cheol | Kim, Seung Hoon

Article Type: Research Article

Abstract: Background: Among the older adults, hearing impairment is a common problem and may contribute to dementia. Objective: Therefore, we aimed to examine the association between hearing impairment and the risk of dementia among older adults in South Korea. Methods: Using the Korean National Health Insurance Service-Senior Cohort from 2005 to 2019, we collected data of 44,728 patients. Hearing impairment was determined using the national disability registry. Propensity score matching (1:1) was performed to match patients with and without hearing impairment (case: 22,364, control: 22,364). A Cox proportional hazards regression model was built to analyze the association …between hearing impairment and dementia. Results: Patients with hearing impairment had a higher risk of dementia than those without hearing impairment (hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.23–1.34). Assessing the degree of disability, both severe (HR = 1.25, 95% CI = 1.16–1.35) and mild conditions (HR = 1.29, 95% CI = 1.23–1.35) had an increased risk of dementia, respectively. Conclusions: Older patients with hearing impairment exhibit an increased risk of dementia, thereby warranting a new approach to dementia care among these patients regardless of the degree of hearing impairment. Show more

Keywords: Alzheimer’s disease, dementia, hearing impairment, hearing loss

DOI: 10.3233/JAD-230816

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 679-686, 2024

Authors: Morin, Peter | Aguilar, Byron J. | Li, Xuyang | Chen, Jinying | Berlowitz, Dan | Zhang, Raymond | Tahami Monfared, Amir Abbas | Zhang, Quanwu | Xia, Weiming

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and related dementias are progressive neurological disorders with stage-specific clinical features and challenges. An important knowledge gap is the “window of time” within which patients transition from mild cognitive impairment or mild AD to moderate or severe AD. Better characterization/establishment of transition times would help clinicians initiating treatments, including anti-amyloid therapy. Objective: To describe cognitive test score-based AD stage transitions in Veterans with AD in the US Veterans Affairs Healthcare System (VAHS). Methods: This retrospective analysis (2010–2019) identified Veterans with AD from the VAHS Electronic Health Record (EHR) notes. …AD stage was based on Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) Examination scores in the EHR. Results: We identified 296,519 Veterans with cognitive test-based AD staging. Over the 10-year study, the proportion of veterans with MMSE scores declined from 24.9% to 9.5% while those with SLUMS rose from 9.0% to 17.8%; and MoCA rose from 5.0% to 25.4%. The average forward transition times between each stage were approximately 2–4 years, whether assessed by MMSE, MoCA, or SLUMS. Conclusion: The average transition time for cognitive test-based assessments of initial cognitive decline, early-stage AD, and moderate/severe AD in the VAHS is 2–4 years. In view of the short window for introducing disease-modifying therapy and the significant benefits of early treatment of AD, our data suggest a critical need for treatment guidelines in the management of AD. Show more

Keywords: Alzheimer’s disease, amyloid, anti-amyloid therapy, cognitive test, dementia, mild cognitive impairment, mini-mental state examination, montreal cognitive assessment, saint louis university mental status examination, veterans

DOI: 10.3233/JAD-230850

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 687-695, 2024

Authors: Prada Crespo, David | Montejo Carrasco, Pedro | Díaz-Mardomingo, Carmen | Villalba-Mora, Elena | Montenegro-Peña, Mercedes

Article Type: Research Article

Abstract: Background: Loneliness and social isolation are considered public health problems among older individuals. In addition, both increase the risk of developing cognitive impairment and dementia. The Social Loneliness construct has been proposed to refer to these harmful social interaction-related factors. Objective: To define the risk factors of Social Loneliness in individuals with mild cognitive impairment (MCI) and to analyze cognitive, emotional, and functional differences according to the participant’s degree of Social Loneliness. Methods: Through convenience sampling, 105 participants over 60 diagnosed with MCI were selected. The evaluation consisted of anamnesis and a comprehensive …neuropsychological examination. The ESTE-II questionnaire was used to assess Social Loneliness and its three factors: perceived social support, social participation, and use of communication technologies. Personality was measured with the NEO-FFI questionnaire. Results: The predictors of the Social Loneliness factors were as follows; 1) perceived social support (R2  = 0.33): Neuroticism (β= 0.353), depression (β= 0.205), and perceived health (β= 0.133); 2) social participation (R2  = 0.24): Conscientiousness (β= –0.344) and Extraversion (β= –0.263); 3) use of communication technologies (R2  = 0.44): age (β= 0.409), type of cohabitation (β= 0.331), cognitive reserve (β= –0.303), and Conscientiousness (β= –0.247); all p  < 0.05. The participants with a higher degree of Social Loneliness showed more depressive symptoms (R2  = 0.133), more memory complaints (R2  = 0.086), worse perceived health (R2  = 0.147), lower attentional performance/processing speed (R2  = 0.094), and more naming difficulties (R2  = 0.132); all p  < 0.05. Conclusions: This research represents an advance in detecting individuals with MCI and an increased risk of developing Social Loneliness, which influences the configuration of the clinical profile of MCI. Show more

Keywords: Aging, Alzheimer's disease, dementia, loneliness, mild cognitive impairment, risk factors, social isolation

DOI: 10.3233/JAD-230901

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 697-714, 2024

Authors: Torkpoor, Rozita | Frolich, Kristin | Londos, Elisabet | Nielsen, T. Rune

Article Type: Research Article

Abstract: Background: Cognitive assessment for foreign-born individuals is suboptimal. The Multicultural Cognitive Examination (MCE) was developed for use in culturally, linguistically and educationally diverse populations. The MCE includes the Rowland Universal Dementia Assessment Scale (RUDAS) and performs assessment of memory, verbal fluency, and visuospatial function. Objective: To compare the psychometric properties of the Swedish version of the Multicultural Cognitive Examination (MCE-S) with the Swedish versions of the RUDAS (RUDAS-S), the Mini-Mental State Examination (MMSE-SR), and the Clock Drawing Test (CDT), and to explore the ability of the MCE-S test to differentiate patients with and without dementia in a multicultural …population. Methods: 117 outpatients at four memory clinics were tested using the MCE-S to complement the routine cognitive assessment. Results: Significant differences between patients with and without dementia were observed for all MCE-S components. There were significant differences between foreign-born and Swedish-born patients in the MMSE-SR, but not in the MCE-S or the RUDAS-S. The MCE-S, had good diagnostic performance for detecting dementia (AUC, 0.82), and was at least as good as the RUDAS-S alone (AUC, 0.79). The MCE-S also distinguished Alzheimer’s disease (AD) from non-AD dementia. Contrary to expectations, the MCE-S was also at least as good as the MMSE-SR among the Swedish-born patients. Conclusions: The MCE-S is adequate for detecting dementia in both foreign-born and Swedish-born populations. Based on the cultural diversity of general society, adapted cognitive tests that can be used for everyone are practical and beneficial for both patients and health-care professionals. Further studies are needed within primary care. Show more

Keywords: Alzheimer’s disease, assessment, cognition, dementia, ethnic minorities, immigrants, multicultural cognitive examination

DOI: 10.3233/JAD-230998

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 715-726, 2024

Authors: Chen, Meimei | Wang, Fengzhen | Lei, Huangwei | Yang, Zhaoyang | Li, Candong

Article Type: Research Article

Abstract: Background: The taxus chinensis fruit (TCF) shows promises in treatment of aging-related diseases such as Alzheimer’s disease (AD). However, its related constituents and targets against AD have not been deciphered. Objective: This study was to uncover constituents and targets of TCF extracts against AD. Methods: An integrated approach including ultrasound extractions and constituent identification of TCF by UPLC-QE-MS/MS, target identification of constituents and AD by R data-mining from Pubchem, Drugbank and GEO databases, network construction, molecular docking and the ROC curve analysis was carried out. Results: We identified 250 compounds in TCF extracts, and …obtained 3,231 known constituent targets and 5,326 differential expression genes of AD, and 988 intersection genes. Through the network construction and KEGG pathway analysis, 19 chemicals, 31 targets, and 11 biological pathways were obtained as core compounds, targets and pathways of TCF extracts against AD. Among these constituents, luteolin, oleic acid, gallic acid, baicalein, naringenin, lovastatin and rutin had obvious anti-AD effect. Molecular docking results further confirmed above results. The ROC AUC values of about 87% of these core targets of TCF extracts was greater than 0.5 in the two GEO chips of AD, especially 10 targets with ROC AUC values greater than 0.7, such as BCL2, CASP7, NFKBIA, HMOX1, CDK2, LDLR, RELA, and CCL2, which mainly referred to neuron apoptosis, response to oxidative stress and inflammation, fibroblast proliferation, etc. Conclusions: The TCF extracts have diverse active compounds that can act on the diagnostic genes of AD, which deserve further in-depth study. Show more

Keywords: Alzheimer’s disease, GEO gene chips, molecular docking, network construction, ROC curve analysis, UPLC-QE-MS/MS

DOI: 10.3233/JAD-231066

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 727-740, 2024

Authors: Mazzola, Paolo | Zanetti, Mariella | Ferraguzzi, Gaia | Villa, Maria Letizia | Sandrini, Maria Cristina | Fumagalli, Marco | Volpi, Maurizio | Caggiu, Giulia | Monzio Compagnoni, Matteo | Mecocci, Patrizia | Bellelli, Giuseppe

Article Type: Research Article

Abstract: Background: Il Paese Ritrovato is an Italian nursing home founded in 2018, it is based on the Alzheimer village model and admits people with mild-to-moderate dementia. Objective: Describe the impact of the SARS-CoV-2 pandemic on people living at Il Paese Ritrovato through a Comprehensive Geriatric Assessment (CGA) regularly administered prior to and during the pandemic. Methods: We explored the effects of a person-centered approach. We assessed 64 subjects (enrolled and followed between June 2018 and December 2020), who underwent at least 18 months of observation prior to the pandemic. Each subject was evaluated using …a CGA on admission time (T0 ) and at defined time-points: T6 , T12 , T18 . One last CGA evaluation was performed during the SARS-CoV-2 pandemic (TCovid-19 ). Temporal trends during T0 –T18 , and differences between T18 and TCovid-19 were calculated. Results: The mean age was 82 years with a prevalence for females (77.0%) and Alzheimer’s disease diagnosis (60%). Psychiatric and behavioral disorders were the most common conditions (80%). We utilized a nonpharmacological approach aimed at promoting the residents’ overall wellbeing and observed satisfactory performance during the first 18 months. In comparison with the pre-pandemic period, TCovid-19 enlightened +11.7% use of antidepressants and a decline of Mini-Mental State Examination mean values (not statistically significant), while engagement in activities dropped. Conclusions: The pandemic may have disrupted the existing model of care, but at the same time, it confirmed that the Il Paese Ritrovato approach, which encompasses symptoms improvement and multicomponent support, is in fact beneficial. Show more

Keywords: Alzheimer’s disease, Alzheimer’s village, comprehensive geriatric assessment, italy, pandemic, SARS-CoV-2

DOI: 10.3233/JAD-230229

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 741-752, 2024

Authors: Safieh, Mirna | Liraz, Ori | Ovadia, Maayan | Michaelson, Danny

Article Type: Research Article

Abstract: Background: Apolipoprotein E4 (APOE4 ) is the most prevalent genetic risk factor of Alzheimer’s disease. Several studies suggest that APOE4 binding to its receptors is associated with their internalization and accumulation in intracellular compartments. Importantly, this phenomenon also occurs with other, non-ApoE receptors. Based on these observations, we hypothesized that APOE4 pathological effects are mediated by impairment in the life cycle of distinct receptors (APOER2, LRP1, IR, VEGFR). Objective: To examine the effects of APOE genotype on receptors protein levels and compartmentalization. Methods: Primary mouse neurons were prepared from APOE3 …or APOE4 targeted replacement mice, or APOE -KO mice. Specific receptors protein levels were evaluated in these neurons, utilizing immunofluorescent staining. Additionally, surface membrane protein levels of those receptors were assessed by cell surface biotinylation assay and ELISA. Receptors’ colocalization with intracellular compartments was assessed by double staining and confocal microscopy, followed by colocalization analysis. Finally, LRP1 or APOER2 were knocked-down with CRISPR/Cas9 system to examine their role in mediating APOE4 effects on the receptors. Results: Our results revealed lower receptors’ levels in APOE4 , specifically on the membrane surface. Additionally, APOE4 affects the compartmentation of these receptors in two patterns: the first was observed with LRP1 and was associated with decreased receptor levels in numerous intracellular compartments. The second was obtained with the other receptors and was associated with their accumulation in early endosomes and their decrease in the late endosomes. Conclusions: These results provide a unifying mechanism, in which APOE4 drives the down regulation of various receptors, which plays important roles in distinct APOE4 related pathological processes. Show more

Keywords: ABCA1, Alzheimer’s disease, APOE4 pathology, APOER2, Apolipoprotein E4, insulin receptors, LRP1, lipidation, receptor recycling, VEGFR

DOI: 10.3233/JAD-230514

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 753-775, 2024

Authors: Ahmed, Tahera | Zhang, Ping | Kumar, Kuldeep

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a particular type of dementia that currently lacks a definitive treatment and cure. It is possible to reduce the risk of developing AD and mitigate its severity through modifications to one’s lifestyle, regular diet, and alcohol-drinking habits. Objective: The objective of this study is to examine the daily dietary patterns of individuals with AD compared to healthy controls, with a focus on nutritional balance and its impact on AD. Methods: This study incorporated multiple-factor analysis (MFA) to evaluate dietary patterns and employed Random Forest (RF) classifier and Sparse …Logistic Regression (SLR) for Variable Importance analysis to identify food items significantly associated with AD. Results: MFA revealed trends in the data and a strong correlation (Lg = 0.92, RV = 0.65) between the daily consumption of processed food and meat items in AD patients. In contrast, no significant relationship was found for any daily consumed food categories within the healthy control (HC) group. Food items such as meat pie, hamburger, ham, sausages, beef, capsicum, and cabbage were identified as important variables associated with AD in RF and SLR analyses. Conclusions: The findings from MFA indicated that the diversity or equilibrium of daily diet might play a potential role in AD development. RF and SLR classifications exhibit among the processed foods, especially deli meats and food made with meat items, are associated with AD. Show more

Keywords: AIBL database, Alzheimer’s disease, dietary habits, multiple factor analysis, random forest, sparse logistic regression

DOI: 10.3233/JAD-230634

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 777-790, 2024

Authors: Schröder, Valerie E. | Skrozic, Amna | Erz, Dorothee | Kaysen, Anne | Fritz, Joëlle V. | Loureiro, Joao M. | McIntyre, Deborah | Pauly, Laure | Kemp, Jennifer | Schmitz, Sabine K. | Wagner, Sophie | Reyes, Margarita | Soare, Ruxandra | Satagopam, Venkata | Vega, Carlos | Gawron, Piotr | Roomp, Kirsten | Conde, Patricia Martins | Klucken, Jochen | Köhler, Sebastian | Hartmann, Tobias | Dodel, Richard | Leist, Anja K. | Kalbe, Elke | Krüger, Rejko

Article Type: Research Article

Abstract: Background: With continuously aging societies, an increase in the number of people with cognitive decline is to be expected. Aside from the development of causative treatments, the successful implementation of prevention strategies is of utmost importance to reduce the high societal burden caused by neurodegenerative diseases leading to dementia among which the most common cause is Alzheimer’s disease. Objective: The aim of the Luxembourgish “programme dementia prevention (pdp )” is to prevent or at least delay dementia in an at-risk population through personalized multi-domain lifestyle interventions. The current work aims to provide a detailed overview of the methodology …and presents initial results regarding the cohort characteristics and the implementation process. Methods: In the frame of the pdp , an extensive neuropsychological evaluation and risk factor assessment are conducted for each participant. Based on the results, individualized multi-domain lifestyle interventions are suggested. Results: A total number of 450 participants (Mean age = 69.5 years; SD = 10.8) have been screened at different recruitment sites throughout the country, among whom 425 participants (94.4%) met the selection criteria. Conclusions: We provide evidence supporting the feasibility of implementing a nationwide dementia prevention program and achieving successful recruitment of the target population by establishing a network of different healthcare providers. Show more

Keywords: Alzheimer’s disease, cognition, dementia prevention, healthy aging, mild cognitive impairment, multi-domain lifestyle interventions, neuropsychological assessment, personalized prevention, risk factor assessment, subjective cognitive decline

DOI: 10.3233/JAD-230794

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 791-804, 2024

Authors: Li, Kuan-Ying | Lin, Bin-Tse | Hsu, Shu-Ting | Chien, Ching-Fang | Chang, Yang-Pei | Yang, Yuan-Han

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are distressing for patients with dementia, often accelerating functional decline and nursing home placement. Medications such as quetiapine are used to alleviate NPS, but their side effects require cautious use. Liquid formulations such as quetiapine oral suspension suit specific populations; however, real-world data on their use in patients with dementia are limited. Objective: The purpose of this retrospective, naturalistic study was to provide preliminary data on the effects of treatment with quetiapine oral suspension on behavioral and psychiatric disturbances in Alzheimer’s disease (AD) outpatients in Taiwan. Methods: Between January 2022 and June …2023, data were collected from outpatients with a diagnosis of probable AD who received treatment with Qting® (quetiapine oral solution 25 mg/ml). Primary outcome measures were changes in Neuropsychiatric Inventory (NPI) total score and its sub-items from baseline to the endpoint. Results: We recruited 66 AD patients with a mean age of 72.1±7.6 years, most of whom were female (69.7%). Twenty-three patients had data on neuropsychological test and NPI scores before and after quetiapine treatment. There was no significant change in global cognitive function from baseline to the endpoint. A significant reduction in NPI total score after quetiapine treatment was noted, while the effect on NPI sub-items was limited. The average maintenance dose was 1.5±0.6 ml. Conclusions: We demonstrated our clinical experience of the use of quetiapine oral solution in AD patients with NPS. Our results showed that quetiapine oral solution treatment significantly improved these symptoms at a relatively low dose. Show more

Keywords: Alzheimer’s disease, antipsychotic, liquid, neuropsychiatric symptoms, quetiapine

DOI: 10.3233/JAD-231007

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 805-811, 2024

Authors: Zhang, Erdong | Dai, Fengqiu

Article Type: Research Article

Abstract: Background: The pathophysiology of Alzheimer’s disease (AD) involves the interplay of three different processes: pyroptosis, apoptosis, and necroptosis. Objective: To explore role of PANoptosis, a novel pro-inflammatory programmed cell death pathway, in AD patients. Methods: We performed a consensus clustering analysis to identify distinct transcriptional profiles in the samples using the R package “ConsensusClusterPlus”. The PANoptosis key genes were obtained by crossing the WGCNA brown module and differentially expressed PANoptosis genes. We accomplished regression analyses using the LASSO-Cox method, combined with pathological status and gene expression data. At the same time, we also constructed PANscore system. …The expression of PANoptosis hub genes were validated by qRT-PCR in AD transgenic mice. Results: Our study utilized tissue expression profile data from AD patients to construct three distinct PANoptosis patterns, each with unique molecular and clinical characteristics. We have created a risk scoring system called PANscore, which can analyze patterns specific for each AD patient. Additionally, we observed significantly lower levels of follicular helper T (Tfh) cells in the high PANscore and AD patients. Further analysis revealed a significant negative correlation of Tfh with GSDMD and MLKL . Conclusions: These findings provide a roadmap for personalized patient stratification, enabling clinicians to develop personalized treatment plans for AD patients and advance the field of precision medicine. Show more

Keywords: Alzheimer’s disease, diagnostic, infiltrating immune cells, PANoptosis, PANscore

DOI: 10.3233/JAD-231103

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 813-828, 2024

Authors: Raji, Cyrus A. | Meysami, Somayeh | Hashemi, Sam | Garg, Saurabh | Akbari, Nasrin | Ahmed, Gouda | Chodakiewitz, Yosef Gavriel | Nguyen, Thanh Duc | Niotis, Kellyann | Merrill, David A. | Attariwala, Rajpaul

Article Type: Research Article

Abstract: Background: The potential neuroprotective effects of regular physical activity on brain structure are unclear, despite links between activity and reduced dementia risk. Objective: To investigate the relationships between regular moderate to vigorous physical activity and quantified brain volumes on magnetic resonance neuroimaging. Methods: A total of 10,125 healthy participants underwent whole-body MRI scans, with brain sequences including isotropic MP-RAGE. Three deep learning models analyzed axial, sagittal, and coronal views from the scans. Moderate to vigorous physical activity, defined by activities increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes …via partial correlations. Analyses adjusted for age, sex, and total intracranial volume, and a 5% Benjamini-Hochberg False Discovery Rate addressed multiple comparisons. Results: Participant average age was 52.98±13.04 years (range 18–97) and 52.3% were biologically male. Of these, 7,606 (75.1%) reported engaging in moderate or vigorous physical activity approximately 4.05±3.43 days per week. Those with vigorous activity were slightly younger (p  < 0.00001), and fewer women compared to men engaged in such activities (p  = 3.76e-15). Adjusting for age, sex, body mass index, and multiple comparisons, increased days of moderate to vigorous activity correlated with larger normalized brain volumes in multiple regions including: total gray matter (Partial R  = 0.05, p  = 1.22e-7), white matter (Partial R  = 0.06, p  = 9.34e-11), hippocampus (Partial R  = 0.05, p  = 5.96e-7), and frontal, parietal, and occipital lobes (Partial R  = 0.04, p ≤1.06e-5). Conclusions: Exercise-related physical activity is associated with increased brain volumes, indicating potential neuroprotective effects. Show more

Keywords: Alzheimer’s disease, brain volumes, deep learning, magnetic resonance imaging, physical activity

DOI: 10.3233/JAD-230740

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 829-839, 2024

Authors: El Haffaf, Lyna Mariam | Ronat, Lucas | Cannizzaro, Adriana | Hanganu, Alexandru

Article Type: Research Article

Abstract: Background: Hyperactive neuropsychiatric symptoms (NPS) (i.e., agitation, disinhibition, and irritability) are among the most challenging symptoms to manage in Alzheimer’s disease (AD). However, their underlying brain correlates have been poorly studied. Objective: We aimed to investigate the associations between the total score of hyperactive NPS and brain structures in participants with AD, mild cognitive impairment (MCI), and cognitively normal older adults (CN). Methods: Neuropsychiatric and 3T MRI data from 216 AD, 564 MCI, and 660 CN participants were extracted from the Alzheimer’s Disease Neuroimaging Initiative database. To define NPS and brain structures’ associations, …we fitted a general linear model (GLM) in two ways: 1) an overall GLM including all three groups (AD, MCI, CN) and 2) three pair-wise GLMs (AD versus MCI, MCI versus CN, AD versus CN). The cortical changes as a function of NPS total score were investigated using multiple regression analyses. Results: Results from the overall GLM include associations between 1) agitation and the right parietal supramarginal surface area in the MCI-CN contrast, 2) disinhibition and the cortical thickness of the right frontal pars opercularis and temporal inferior in the AD-MCI contrast, and 3) irritability and the right frontal pars opercularis , frontal superior, and temporal superior volumes in the MCI-CN contrast. Conclusions: Our study shows that each hyperactive NPS is associated with distinct brain regions in AD, MCI, and CN (groups with different levels of cognitive performance). This suggests that each NPS is associated with a unique signature of brain morphology, including variations in volume, thickness, or area. Show more

Keywords: Agitation, Alzheimer’s disease, cognitively normal older adults, cortical structures, disinhibition, irritability, magnetic resonance imaging, mild cognitive impairment, neuropsychiatric symptoms

DOI: 10.3233/JAD-220857

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 841-853, 2024

Authors: Britz, Jesse | Ojo, Emmanuel | Haque, Nazmul | Dhukhwa, Asmita | Hascup, Erin R. | Hascup, Kevin N. | Tischkau, Shelley A.

Article Type: Research Article

Abstract: Background: Chronic disruption of the circadian timing system, often reflected as a loss of restful sleep, also includes myriad other pathophysiological effects. Objective: The current study examined how chronic circadian disruption (CD) could contribute to pathology and rate of progression in the AβPP/PS1 mouse model of Alzheimer’s disease (AD). Methods: A chronic CD was imposed until animals reached 6 or 12 months of age in AβPP/PS1 and C57BL/6J control mice. Home cage activity was monitored for a period of 3–4 weeks prior to the endpoint along with a single timepoint measure of glucose sensitivity. To assess …long term effects of CD on the AD phenotype, animals were re-entrained to a no disruption (ND) schedule just prior to the endpoint, after which a Morris water maze (MWM) was used to assess spatial learning and memory. Results: Dampening of nighttime activity levels occurred in disrupted animals, and female animals demonstrated a greater adaptability to CD. Diminished arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) levels in the suprachiasmatic nucleus (SCN) of 12-month male AβPP/PS1 exposed to the CD paradigm were observed, potentially accounting for the diminished re-entrainment response. Similarly, CD worsened performance in the MWM in 12-month male AβPP/PS1 animals, whereas no effect was seen in females. Conclusions: Collectively, these findings show that exposure to chronic CD impairs circadian behavioral patterns and cognitive phenotypes of AβPP/PS1 mouse model in a sex-dependent manner. Show more

Keywords: Alzheimer’s disease, amyloid-β, arginine vasopressin, circadian disruption, circadian rhythm, cognition, glial fibrillary acidic protein, metabolism, vasoactive intestinal peptide

DOI: 10.3233/JAD-230089

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 855-870, 2024

Authors: Miyano, Takashi | Ayukawa, Yasunori | Anada, Takahisa | Takahashi, Ichiro | Furuhashi, Hiroko | Tokunaga, Shoji | Hirata, Akie | Nakashima, Naoki | Kato, Koichiro | Fukuda, Haruhisa

Article Type: Research Article

Abstract: Background: An association between poor oral health and cognitive decline has been reported. Most of these studies have considered the number of teeth as a criterion, only a few studies have analyzed the relationship between occlusal status and Alzheimer’s disease (AD). Objective: To elucidate whether posterior occlusal contact is associated with AD, focusing on the Eichner classification, among an older population aged 65 years or older in Japan. Methods: This study used monthly claims data of National Health Insurance in Japan from April 2017 to March 2020. The outcome was newly diagnosed AD …defined according to ICD-10 code G30. The number of teeth was estimated by dental code data, and occlusal contact was divided into three categories, namely A, B, and C, according to the Eichner classification. Multivariate Cox proportional hazards models were used to analyze the association between a new diagnosis of AD and the Eichner classification. Results: A total of 22,687 participants were included, 560 of whom had newly diagnosed AD during a mean follow-up period of 12.2 months. The AD participants had a lower proportion of Eichner A and a higher proportion of Eichner C. After adjusting for covariates, hazard ratios (95% confidence intervals) with Eichner B and C were 1.34 (1.01–1.77) and 1.54 (1.03–2.30), respectively. Conclusion: In older people aged≥65 years old, reduced posterior occlusal contact as well as tooth loss have an impact on AD. This study emphasizes the importance of paying attention to occlusal contacts to reduce the risk of AD. Show more

Keywords: Alzheimer’s disease, eichner classification, healthcare administrative claims, occlusal contacts

DOI: 10.3233/JAD-230449

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 871-881, 2024

Authors: Fan, Xiang | Cai, Yuan | Zhao, Lei | Liu, Wanting | Luo, Yishan | Au, Lisa Wing Chi | Shi, Lin | Mok, Vincent Chung Tong

Article Type: Research Article

Abstract: Background: Pilot study showed that Alzheimer’s disease resemblance atrophy index (AD-RAI), a machine learning-derived MRI-based neurodegeneration biomarker of AD, achieved excellent diagnostic performance in diagnosing AD with moderate to severe dementia. Objective: The primary objective was to validate and compare the performance of AD-RAI with conventional volumetric hippocampal measures in diagnosing AD with mild dementia. The secondary objectives were 1) to investigate the association between imaging biomarkers with age and gender among cognitively unimpaired (CU) participants; 2) to analyze whether the performance of differentiating AD with mild dementia from CU will improve after adjustment for age/gender. …Methods: AD with mild dementia (n  = 218) and CU (n  = 1,060) participants from 4 databases were included. We investigated the area under curve (AUC), sensitivity, specificity, and balanced accuracy of AD-RAI, hippocampal volume (HV), and hippocampal fraction (HF) in differentiating between AD and CU participants. Among amyloid-negative CU participants, we further analyzed correlation between the biomarkers with age/gender. We also investigated whether adjustment for age/gender will affect performance. Results: The AUC of AD-RAI (0.93) was significantly higher than that of HV (0.89) and HF (0.89). Subgroup analysis among A + AD and A- CU showed that AUC of AD-RAI (0.97) was also higher than HV (0.94) and HF (0.93). Diagnostic performance of AD-RAI and HF was not affected by age/gender while that of HV improved after age adjustment. Conclusions: AD-RAI achieves excellent clinical validity and outperforms conventional volumetric hippocampal measures in aiding the diagnosis of AD mild dementia without the need for age adjustment. Show more

Keywords: Alzheimer’s disease, machine learning, mild dementia, MRI, sensitivity and specificity

DOI: 10.3233/JAD-230574

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 883-893, 2024

Authors: Robinson, Carling G. | Coleman, Tia | Buciuc, Marina | Singh, Neha Atulkumar | Pham, Nha Trang Thu | Machulda, Mary M. | Graff-Radford, Jonathan | Whitwell, Jennifer L. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two common atypical Alzheimer’s disease (AD) variants. Little is known about behavioral and neuropsychiatric symptoms or activities of daily living (ADLs) in PCA and LPA, and whether they differ across syndromes. Objective: To characterize the behavioral and neuropsychiatric profiles and ADLs of PCA and LPA and compare presence/absence and severity of symptoms between syndromes. Methods: Seventy-eight atypical AD patients, 46 with PCA and 32 with LPA, completed the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Cambridge Behavioral Inventory-Revised (CBI-R) at baseline and longitudinally over-time. Mann-Whitney U and …Fisher’s Exact Tests assessed for differences in symptoms between the two syndromes with significance set at p ≤0.01. To eliminate demographic differences as confounders the groups were matched, and differences reanalyzed. Results: PCA were younger at onset (p  = 0.006), at time of baseline assessment (p  = 0.02) and had longer disease duration (p  = 0.01). Neuropsychiatric symptoms were common in PCA and LPA, although more common and severe in PCA. At baseline, PCA had a higher NPI-Q total score (p  = 0.01) and depression subscore (p  = 0.01) than LPA. Baseline total CBI-R scores were also higher in PCA than LPA (p  = 0.001) with PCA having worse scores in all 10 CBI-R categories. Longitudinally, there was no difference between groups on the NPI-Q. However, on the CBI-R, PCA had faster rates of worsening on self-grooming (p  = 0.01) and self-dressing (p  = 0.01) compared to LPA. Conclusions: Behavioral and neuropsychiatric symptoms are common in PCA and LPA although these symptoms are more common and severe in PCA. Show more

Keywords: Alzheimer’s disease, atypical Alzheimer’s disease, behavioral, logopenic progressive aphasia, neuropsychiatric, posterior cortical atrophy

DOI: 10.3233/JAD-230652

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 895-908, 2024

Authors: Fan, Xinxin | Li, Haining | Liu, Lin | Zhang, Kai | Zhang, Zhewei | Chen, Yi | Wang, Zhen | He, Xiaoli | Xu, Jinping | Hu, Qingmao

Article Type: Research Article

Abstract: Background: Structural magnetic resonance imaging (sMRI) is vital for early Alzheimer’s disease (AD) diagnosis, though confirming specific biomarkers remains challenging. Our proposed Multi-Scale Self-Attention Network (MUSAN) enhances classification of cognitively normal (CN) and AD individuals, distinguishing stable (sMCI) from progressive mild cognitive impairment (pMCI). Objective: This study leverages AD structural atrophy properties to achieve precise AD classification, combining different scales of brain region features. The ultimate goal is an interpretable algorithm for this method. Methods: The MUSAN takes whole-brain sMRI as input, enabling automatic extraction of brain region features and modeling of correlations …between different scales of brain regions, and achieves personalized disease interpretation of brain regions. Furthermore, we also employed an occlusion sensitivity algorithm to localize and visualize brain regions sensitive to disease. Results: Our method is applied to ADNI-1, ADNI-2, and ADNI-3, and achieves high performance on the classification of CN from AD with accuracy (0.93), specificity (0.82), sensitivity (0.96), and area under curve (AUC) (0.95), as well as notable performance on the distinguish of sMCI from pMCI with accuracy (0.85), specificity (0.84), sensitivity (0.74), and AUC (0.86). Our sensitivity masking algorithm identified key regions in distinguishing CN from AD: hippocampus, amygdala, and vermis. Moreover, cingulum, pallidum, and inferior frontal gyrus are crucial for sMCI and pMCI discrimination. These discoveries align with existing literature, confirming the dependability of our model in AD research. Conclusion: Our method provides an effective AD diagnostic and conversion prediction method. The occlusion sensitivity algorithm enhances deep learning interpretability, bolstering AD research reliability. Show more

Keywords: Alzheimer’s disease, deep learning, explainable deep learning, multilevel feature learning, structural MRI

DOI: 10.3233/JAD-230705

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 909-926, 2024

Authors: Gao, Ju | Leinonen, Henri | Wang, Evan J. | Ding, Mao | Perry, George | Palczewski, Krzysztof | Wang, Xinglong

Article Type: Research Article

Abstract: Background: Increasing evidence has highlighted retinal impairments in neurodegenerative diseases. Dominant mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the accumulation of TDP-43 in the cytoplasm is a pathological hallmark of ALS, frontotemporal dementia (FTD), and many other neurodegenerative diseases. Objective: While homozygous transgenic mice expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) experience premature death, hemizygous TDP-43M337V mice do not suffer sudden death, but they exhibit age-dependent motor-coordinative and cognitive deficits. This study aims to leverage the hemizygous TDP-43M337V mice as a valuable ALS/FTD disease model for the …assessment also of retinal changes during the disease progression. Methods: We evaluated the retinal function of young TDP-43M337V mice by full field electroretinogram (ERG) recordings. Results: At 3–4 months of age, well before the onset of brain dysfunction at 8 months, the ERG responses were notably impaired in the retinas of young female TDP-43M337V mice in contrast to their male counterparts and age-matched non-transgenic mice. Mitochondria have been implicated as critical targets of TDP-43. Further investigation revealed that significant changes in the key regulators of mitochondrial dynamics and bioenergetics were only observed in the retinas of young female TDP-43M337V mice, while these alterations were not present in the brains of either gender. Conclusions: Together our findings suggest a sex-specific vulnerability within the retina in the early disease stage, and highlight the importance of retinal changes and mitochondrial markers as potential early diagnostic indicators for ALS, FTD, and other TDP-43 related neurodegenerative conditions. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, mitochondrial dynamics, OXPHOS, retina, sex differences, TDP-43

DOI: 10.3233/JAD-231102

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 927-937, 2024

Authors: Dingle, Sara E. | Milte, Catherine M. | Daly, Robin M. | Torres, Susan J.

Article Type: Research Article

Abstract: Background: Dementia, with the most common form being Alzheimer’s disease, is a global health issue and lifestyle-based strategies may reduce risk. Individuals with a family history of dementia are an important target group, but little is known about their attitudes and perceptions of dementia risk reduction. Objective: To elucidate the attitudes to and key considerations for multidomain lifestyle-based dementia prevention strategies in middle-aged Australians with a family history of dementia. Methods: Twenty participants (80% female; age range 47–65 years), undertook semi-structured phone-based interviews. Inductive thematic analysis of interview transcripts was conducted. Hierarchical coding …frames and illustrative quotes were compiled and critically challenged until a final set of themes was produced. Results: Some participants expressed a positive attitude toward lifestyle-based dementia prevention. Reasons related to wanting to future proof, believing that risk reduction is relevant at all life stages and/or that there is always room for improvement. Other participants had a negative attitude, expressing that they were already following a healthy lifestyle, did not feel it was relevant to them yet, and/or held a deterministic view that dementia is random. Important considerations congregated on the themes of being tailored/personalized, taking a holistic approach, and involving small, achievable steps. Conclusions: In individuals with a family history of dementia, a positive attitude to dementia prevention holds promise for intervention efforts, but in individuals expressing negative attitudes, further education and individual-level counselling may be warranted. Multidomain lifestyle-based preventive strategies also need to be tailored to the needs of key target groups to optimize appeal and effectiveness. Show more

Keywords: Alzheimer’s disease, dementia, lifestyle, prevention, qualitative study

DOI: 10.3233/JAD-230176

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 939-949, 2024

Authors: de la Perrelle, Lenore

Article Type: Article Commentary

Abstract: With an aging population, an increase in cases of Alzheimer’s disease and dementia worldwide poses a significant health burden. While we hope for a cure, preventing dementia by reducing risks is important for global population health. Prevention strategies are difficult to implement when facing inequality across the world for access to healthy lifestyles. An approach that centers on individual responsibility and health professional interventions for targeted groups may risk missing the policy and environmental drivers of change. Barriers and enablers need to be explored and interventions are needed at individual, structural and social levels to normalize mid-life risk reduction.

Keywords: Alzheimer’s disease, dementia risk reduction, family history, mid-life strategies, multidomain interventions

DOI: 10.3233/JAD-231348

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 951-952, 2024

Authors: Frentz, Ingeborg | van Arendonk, Joyce | Leeuwis, Anna E. | Vernooij, Meike W. | van der Flier, Wiesje M. | Bos, Daniel | De Deyn, Peter Paul | Wolters, Frank J. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Dementia is a multifactorial disease, with Alzheimer’s disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined. Objective: The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia. Methods: We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) cross-sectionally. Results: Amyloid-β (Aβ)42 …and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ42 and between arterial calcification and the ratio of Aβ42/40 . Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors. Conclusions: Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment. Show more

Keywords: Alzheimer’s disease, amyloid-β, arteriosclerosis, calcification, dementia, plasma biomarkers

DOI: 10.3233/JAD-230604

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 953-961, 2024

Authors: de Boer, Sterre C.M. | Riedl, Lina | Fenoglio, Chiara | Rue, Ishana | Landin-Romero, Ramon | Matis, Sophie | Chatterton, Zac | Galimberti, Daniela | Halliday, Glenda | Diehl-Schmid, Janine | Piguet, Olivier | Pijnenburg, Yolande A.L. | Ducharme, Simon

Article Type: Research Article

Abstract: Background: The behavioral variant of frontotemporal dementia (bvFTD) is very heterogeneous in pathology, genetics, and disease course. Unlike Alzheimer’s disease, reliable biomarkers are lacking and sporadic bvFTD is often misdiagnosed as a primary psychiatric disorder (PPD) due to overlapping clinical features. Current efforts to characterize and improve diagnostics are centered on the minority of genetic cases. Objective: The multi-center study DIPPA-FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late-onset PPD in its earliest stages. Methods: The prospective DIPPA-FTD study recruits participants with late-life behavioral changes, suspect for bvFTD or …late-onset PPD diagnosis with a negative family history for FTD and/or amyotrophic lateral sclerosis. Subjects are invited to participate after diagnostic screening at participating memory clinics or recruited by referrals from psychiatric departments. At baseline visit, participants undergo neurological and psychiatric examination, questionnaires, neuropsychological tests, and brain imaging. Blood is obtained to investigate biomarkers. Patients are informed about brain donation programs. Follow-up takes place 10-14 months after baseline visit where all examinations are repeated. Results from the DIPPA-FTD study will be integrated in a data-driven approach to develop diagnostic and prognostic models. Conclusions: DIPPA-FTD will make an important contribution to early sporadic bvFTD identification. By recruiting subjects with ambiguous or prodromal diagnoses, our research strategy will allow the characterization of early disease stages that are not covered in current sporadic FTD research. Results will hopefully increase the ability to diagnose sporadic bvFTD in the early stage and predict progression rate, which is pivotal for patient stratification and trial design. Show more

Keywords: Alzheimer’s disease, diagnostics, frontotemporal dementia, neurodegeneration, prognostics, psychiatric disorders

DOI: 10.3233/JAD-230829

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 963-973, 2024

Article Type: Correction

DOI: 10.3233/JAD-239014

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 975-976, 2024