Journal of Alzheimer's Disease - Volume 98, issue 1

Authors: Shea, Tom | Szaro, Ben

Article Type: Obituary

DOI: 10.3233/JAD-249005

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 1-2, 2024

Authors: Ross, John Paul | Post, Stephen G. | Scheinfeld, Laurel

Article Type: Review Article

Abstract: Background: Even in severe states of Alzheimer’s disease and related dementias (ADRD), accounts of an unexpected or paradoxical return of awareness and lucidity have been reported in some patients, documented formally, and studied. Objective: A scoping review was undertaken to survey the literature on the topic. Methods: Five databases were searched using pertinent search terms. Results were deduplicated and subsequently screened by title and abstract for relevance. Remaining reports were read and included or excluded using specific inclusion criteria. 30 results consisted of a mix of perspective papers, case reports, qualitative surveys of caregivers, law journal …comments, and mechanistic speculation. Results: An equal mix of primary and secondary research was identified. Conclusions: The papers collected in this review provide a valuable methodological outline for researching the topic of lucid episodes in ADRD. The verified legitimacy and simultaneous inexplicability of these events promote philosophical discussion, mechanistic investigations, and sorely needed research in the field of ADRD. Show more

Keywords: Alzheimer’s disease, awareness, caregivers, dementia, lucidity, neurodegenerative disorders, paradoxical lucidity, terminal lucidity, unexpected lucidity

DOI: 10.3233/JAD-231396

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 3-11, 2024

Authors: Li, Zhirui | Fan, Zixuan | Zhang, Qian

Article Type: Systematic Review

Abstract: Background: Cerebrospinal fluid (CSF) or blood biomarkers like phosphorylated tau proteins (p-tau) are used to detect Alzheimer’s disease (AD) early. Increasing studies on cognitive function and blood or CSF p-tau levels are controversial. Objective: Our study examined the potential of p-tau as a biomarker of cognitive status in normal control (NC), mild cognitive impairment (MCI), and AD patients. Methods: We searched PubMed, Cochrane, Embase, and Web of Science for relevant material through 12 January 2023. 5,017 participants from 20 studies—1,033 AD, 2,077 MCI, and 1,907 NC—were evaluated. Quantitative analysis provided continuous outcomes as SMDs with 95% …CIs. Begg tested publication bias. Results: MCI patients had lower CSF p-tau181 levels than AD patients (SMD =−0.60, 95% CI (−0.85, −0.36)) but higher than healthy controls (SMD = 0.67). AD/MCI patients had greater plasma p-tau181 levels than healthy people (SMD =−0.73, 95% CI (−1.04, −0.43)). MCI patients had significantly lower p-tau231 levels than AD patients in plasma and CSF (SMD =−0.90, 95% CI (−0.82, −0.45)). MCI patients showed greater CSF and plasma p-tau231 than healthy controls (SMD = 1.34, 95% CI (0.89, 1.79) and 0.43, (0.23, 0.64)). Plasma p-tau181/231 levels also distinguished the three categories. MCI patients had higher levels than healthy people, while AD patients had higher levels than MCI patients. Conclusions: CSF p-tau181 and p-tau231 biomarkers distinguished AD, MCI, and healthy populations. Plasma-based p-tau181 and p-tau231 biomarkers for AD and MCI need further study. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, mild cognitive impairment, phosphorylated tau 181, phosphorylated tau 231, plasma

DOI: 10.3233/JAD-230799

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 13-32, 2024

Authors: Rossi, Eleonora | Marrosu, Francesco | Saba, Luca

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) is a complex condition that affects various aspects of a patient’s life. Music therapy may be considered a beneficial supplementary tool to traditional therapies, that not fully address the range of AD manifestations. Objective: The purpose of this systematic review is to investigate whether music therapy can have a positive impact on AD patients and on which symptoms. Methods: The main research databases employed have been PubMed and Cochrane, using the keywords “dementia”, “music therapy”, “Alzheimer”, “fMRI”, “music”, and “EEG”. Results: After removing duplicates and irrelevant studies, 23 were screened …using set criteria, resulting in the final inclusion of 15 studies. The total number of participants included in these studies has been of 1,196 patients. For the fMRI analysis the search resulted in 28 studies on PubMed, two of which were included in the research; the total number of participants was of 124 individuals. The studies conducted with EEG were found using PubMed. The initial search resulted in 15 studies, but after a more accurate evaluation only 2 have been included in the analysis. Conclusions: Even though the data currently available is not sufficient to draw conclusions supported by robust statistical power, the impact of music therapy on AD neuropsychiatric symptoms deserves great interest. Further research should be ushered, possibly multicentric studies, led with neuroimaging and other recent techniques, which can eventually open views on the music role in improving the cognitive status in AD. Show more

Keywords: Alzheimer’s disease, cognitive function, dementia, EEG, fMRI, mild cognitive impairment, music therapy, neuropsychiatric symptoms, systematic review

DOI: 10.3233/JAD-230852

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 33-51, 2024

Authors: Cotta Ramusino, Matteo | Scanu, Lucia | Gritti, Linda | Imbimbo, Camillo | Farina, Lisa Maria | Cosentino, Giuseppe | Perini, Giulia | Costa, Alfredo

Article Type: Systematic Review

Abstract: Background: The clinical features of posterior cortical atrophy (PCA), a rare condition often caused by Alzheimer’s disease, have been recently defined, while little is known about its neurophysiological correlates. Objective: To describe neurophysiological alterations of the visual pathway as assessed using visual field test (VF), visual evoked potentials (VEP), and electroretinogram (ERG) in PCA patients. Methods: Studies reporting VF, VEPs, and ERG in PCA patients were selected according PRISMA method. Of the 323 articles that emerged from the literature, 17 included the outcomes of interest. To these data, we added those derived from a patient cohort …enrolled at our clinic. Results: The literature review included 140 patients, half of them (50%) presented with homonymous hemianopia or quadrantanopia. VEPs were available in 4 patients (2 normal findings, 1 decreased amplitude, and 1 increased latency) and ERG in 3 patients (substantially normal findings). Our case series included 6 patients, presenting with homonymous lateral hemianopia in 50% and contralateral cortical atrophy. VEPs showed normal amplitude in 66–83% according to the stimulation check, and increased latency in 67% in absence of myelin damage on MRI. Latency was increased in both eyes in 50% and only on one side in the other 50%. Such alterations were observed in patients with more severe and symmetric atrophy. ERG showed normal findings. Conclusions: Neurophysiological investigations of the visual pathway in PCA are almost absent in literature. Alterations involve both amplitude and latency and can be also monocular. A multiple-point involvement of the optical pathway can be hypothesized. Show more

Keywords: Alzheimer’s disease, electroretinogram, posterior cortical atrophy, visual evoked potentials, visual field

DOI: 10.3233/JAD-231123

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 53-67, 2024

Authors: Gills, Joshua L. | Bubu, Omonigho M.

Article Type: Article Commentary

Abstract: Impairments of the sleep architecture due to disrupted sleep in individuals with obstructive sleep apnea (OSA) may result in reduced slow wave sleep (SWS), intermittent hypoxemia, and excessive day time sleepiness— all factors that have been shown to impact Alzheimer’s disease (AD) risk. In this commentary, we comment on the work by Cavuoto and colleagues in which they examine the associations between nocturnal hypoxemia or sleep disruptions (during SWS) and amyloid-β burden in individuals with OSA. We review the findings in the context of other similar studies and highlight the strengths and weaknesses of these published studies. We note the …importance of examining these relationships longitudinally with a large sample size, including considering sleep health disparities, vascular components, and multiple cognitive domain tests. Show more

Keywords: Alzheimer’s disease, amyloid burden, cognition, obstructive sleep apnea, slow wave sleep

DOI: 10.3233/JAD-231385

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 69-73, 2024

Authors: Siafarikas, Nikias

Article Type: Article Commentary

Abstract: Neuropsychiatric symptoms (NPS) are increasingly being recognized as clinical markers for incipient dementia in Alzheimer’s disease (AD dementia). NPS may reinforce cognitive impairment or decline and vice versa. Although NPS are frequent already in mild cognitive impairment, their mechanisms are poorly understood. It is unclear if they share biological mechanisms with cognitive symptoms and how they are associated to structural brain changes, but evidence suggests associations of NPS to cerebral atrophy. An additional NPS dimension in AD dementia concepts might add valuable information to detect patients at risk for AD dementia.

Keywords: Alzheimer’s disease, cerebral atrophy, dementia, mild cognitive impairment, neuroimaging, neuropsychiatric symptoms

DOI: 10.3233/JAD-231418

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 75-78, 2024

Authors: Talan, Jamie

Article Type: Editorial

Keywords: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, ALSP, ALSP Foundation, cerebral white matter degeneration, CSF1R mutation, Zbigniew K. Wszolek

DOI: 10.3233/JAD-249003

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 79-82, 2024

Authors: Prabhakaran, Divya | Grant, Caroline | Pedraza, Otto | Caselli, Richard | Athreya, Arjun P. | Chandler, Melanie

Article Type: Research Article

Abstract: Background: Identifying individuals at risk for mild cognitive impairment (MCI) is of urgent clinical need. Objective: This study aimed to determine whether machine learning approaches could harness longitudinal neuropsychology measures, medical data, and APOE ɛ 4 genotype to identify individuals at risk of MCI 1 to 2 years prior to diagnosis. Methods: Data from 676 individuals who participated in the ‘APOE in the Predisposition to, Protection from and Prevention of Alzheimer’s Disease’ longitudinal study (N  = 66 who converted to MCI) were utilized in supervised machine learning algorithms to predict conversion to MCI. …Results: A random forest algorithm predicted conversion 1–2 years prior to diagnosis with 97% accuracy (p  = 0.0026). The global minima (each individual’s lowest score) of memory measures from the ‘Rey Auditory Verbal Learning Test’ and the ‘Selective Reminding Test’ were the strongest predictors. Conclusions: This study demonstrates the feasibility of using machine learning to identify individuals likely to convert from normal cognition to MCI. Show more

Keywords: Aging, Alzheimer’s disease, APOE , machine learning, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-230556

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 83-94, 2024

Authors: Yang, Jingjing | Liu, Xizhu | Oveisgharan, Shahram | Zammit, Andrea R. | Nag, Sukriti | Bennett, David A. | Buchman, Aron S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease neuropathologic changes (AD-NC) are important to identify people with high risk for AD dementia (ADD) and subtyping ADD. Objective: Develop imputation models based on clinical measures to infer AD-NC. Methods: We used penalized generalized linear regression to train imputation models for four AD-NC traits (amyloid-β, tangles, global AD pathology, and pathologic AD) in Rush Memory and Aging Project decedents, using clinical measures at the last visit prior to death as predictors. We validated these models by inferring AD-NC traits with clinical measures at the last visit prior to death for independent Religious Orders …Study (ROS) decedents. We inferred baseline AD-NC traits for all ROS participants at study entry, and then tested if inferred AD-NC traits at study entry predicted incident ADD and postmortem pathologic AD. Results: Inferred AD-NC traits at the last visit prior to death were related to postmortem measures with R2  = (0.188,0.316,0.262) respectively for amyloid-β, tangles, and global AD pathology, and prediction Area Under the receiver operating characteristic Curve (AUC) 0.765 for pathologic AD. Inferred baseline levels of all four AD-NC traits predicted ADD. The strongest prediction was obtained by the inferred baseline probabilities of pathologic AD with AUC = (0.919,0.896) for predicting the development of ADD in 3 and 5 years from baseline. The inferred baseline levels of all four AD-NC traits significantly discriminated pathologic AD profiled eight years later with p -values < 1.4×10-10 . Conclusions: Inferred AD-NC traits based on clinical measures may provide effective AD biomarkers that can estimate the burden of AD-NC traits in aging adults. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease neurologic change, computational modeling, dementia, pathology

DOI: 10.3233/JAD-230639

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 95-107, 2024

Authors: Su, Wenlong | Li, Hui | Dang, Hui | Han, Kaiyue | Liu, Jiajie | Liu, Tianhao | Liu, Ying | Tang, Zhiqing | Lu, Haitao | Zhang, Hao

Article Type: Research Article

Abstract: Background: The mechanism(s) of cognitive impairment remains complex, making it difficult to confirm the factors influencing poststroke cognitive impairment (PSCI). Objective: This study quantitatively investigated the degree of influence and interactions of clinical indicators of PSCI. Methods: Information from 270 patients with PSCI and their Wechsler Adult Intelligence Scale (WAIS-RC) scores, totaling 18 indicators, were retrospectively collected. Correlations between the indicators and WAIS scores were calculated. Multiple linear regression model(MLR), genetic algorithm modified Back-Propagation neural network(GA-BP), logistic regression model (LR), XGBoost model (XGB), and structural equation model were used to analyze the degree of influence of …factors on the WAIS and their mediating effects. Results: Seven indicators were significantly correlated with the WAIS scores: education, lesion side, aphasia, frontal lobe, temporal lobe, diffuse lesions, and disease course. The MLR showed significant effect of education, lesion side, aphasia, diffuse lesions, and frontal lobe on the WAIS. The GA-BP included five factors: education, aphasia, frontal lobe, temporal lobe, and diffuse lesions. LR predicted that the lesion side contributed more to mild cognitive impairment, while education, lesion side, aphasia, and course of the disease contributed more to severe cognitive impairment. XGB showed that education, side of the lesion, aphasia, and diffuse lesions contributed the most to PSCI. Aphasia plays a significant mediating role in patients with severe PSCI. Conclusions: Education, lesion side, aphasia, frontal lobe, and diffuse lesions significantly affected PSCI. Aphasia is a mediating variable between clinical information and the WAIS in patients with severe PSCI. Show more

Keywords: Alzheimer’s disease, cognitive impairment, predictor, stroke, WAIS-R

DOI: 10.3233/JAD-230840

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 109-117, 2024

Authors: Ju, In Gyoung | Lee, Seungmin | Kim, Seong Hye | Im, Hyeri | Eo, Hyeyoon | Oh, Myung Sook

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the most common form of dementia, is characterized by memory loss and the abnormal accumulation of senile plaques composed of amyloid-β (Aβ) protein. Trichosanthis Semen (TS) is a traditional herbal medicine used to treat phlegm-related conditions. While TS is recognized for various bioactivities, including anti-neuroinflammatory effects, its ability to attenuate AD remains unknown. Objective: To evaluate the effects of TS extract (TSE) on neuronal damage, Aβ accumulation, and neuroinflammation in AD models. Methods: Thioflavin T and western blot assays were used to assess effects on Aβ aggregation in vitro . TS was …treated to PC12 cells with Aβ to assess the neuroprotective effects. Memory functions and histological brain features were investigated in TSE-treated 5×FAD transgenic mice and mice with intracerebroventricularly injected Aβ. Results: TSE disrupted Aβ aggregation and increased the viability of cells and phosphorylation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) in vitro . TSE treatment also suppressed the accumulation of Aβ plaques in the brain of 5×FAD mice, protected neuronal cells in both the subiculum and medial septum, and upregulated Akt/ERK phosphorylation in the hippocampus. Moreover, TSE ameliorated the memory decline and glial overactivation observed in 5×FAD mice. As assessing whether TS affect Aβ-induced neurotoxicity in the Aβ-injected mice, the effects of TS on memory improvement and neuroinflammatory inhibition were confirmed. Conclusions: TSE disrupted Aβ aggregation, protected neurons against Aβ-induced toxicity, and suppressed neuroinflammation, suggesting that it can suppress the development of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, neuroinflammation, neuroprotection, Trichosanthis semen

DOI: 10.3233/JAD-231124

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 119-131, 2024

Authors: Altomare, Daniele | Rivolta, Jasmine | Libri, Ilenia | Mattioli, Irene | Cantoni, Valentina | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms cause significant suffering and poor quality of life for patients and their caregivers. They are not considered specific to frontotemporal dementia (FTD); therefore, their clinical role and impact might be underestimated. Objective: The aims of the present study are to: 1) describe the prevalence of neuropsychiatric symptoms in FTD starting from the prodromal stage, 2) define their association with disease severity, 3) identify symptoms which are unrelated to FTD-specific symptoms, and 4) assess their association with clinical features and outcomes. Results: In this retrospective study, we analyzed data of 461 FTD patients, including …behavioral variant of FTD (bvFTD, n  = 318) and primary progressive aphasia (PPA, n  = 143). Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory, and patients’ staging and global disease severity were estimated using the Clinical Dementia Rating plus NACC FTLD. Results: The most common neuropsychiatric symptoms in prodromal FTD were irritability (48%), depression (35%), and anxiety (34%); delusions were reported in 6%of prodromal bvFTD cases. The severity of most neuropsychiatric symptoms increased with global disease severity. Psychosis (delusions and hallucinations) and mood symptoms (depression and anxiety) were mostly independent from FTD-specific symptoms. Psychosis was associated with older age, higher disease severity, shorter survival rate, and was higher in bvFTD than in PPA. Conclusions: Neuropsychiatric symptoms are common in patients with FTD, also in the prodromal phase. Psychosis might be unrelated to FTD pathology, and be associated with worse clinical outcomes. The prompt detection and treatment of these symptoms might improve patient’s management and quality of life. Show more

Keywords: Clinical assessment, dementia, diagnosis, prodromal, psychogeriatrics

DOI: 10.3233/JAD-231256

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 133-144, 2024

Authors: Putignano, Salvatore | Forgione, Luigi | Fusco, Mariano | Giacummo, Attilio | Magli, Elisa | Marino, Saverio | Marzano, Raffaele | Putignano, Daria | Santamaria, Francesco | Spatarella, Micaela | Santagada, Vincenzo

Article Type: Research Article

Abstract: Background: Dementia is the fourth leading cause of death in people >  65 years old in western countries. Objective: This cross-sectional assisted survey aimed to evaluate a multidisciplinary team approach of specialists of the Associazione Geriatri Extraospedalieri a favore di Anziani Svantaggiati and pharmacists to facilitate progress in the early identification and management of cognitive decline in patients >  60 years. Methods: A multidisciplinary team conducted this cross-sectional assisted survey. Patients (>60 years) with independent and/or assisted walking, subjective memory impairment, mild cognitive impairment or mild Alzheimer’s disease (AD) who regularly attended pharmacies underwent the survey. An internal …medical examination, a cardiovascular visit, and a short neuropsychological evaluation were conducted for each patient. Demographic, anamnestic, and clinical data were collected anonymously. Results: 279 eligible patients underwent the screening phase. 44% were overweight, 23% obese and 29% hypertensive. 62% of cases showed alterations of supra-aortic trunk with different percentages of stenosis. The neuropsychological evaluation highlighted that 67% of cases were normal according to age and education level, while 18% were in a state condition of cognitive frailty. Mild/moderate cognitive decline, or probably AD, was identified in 14% of cases. Conclusions: A multidisciplinary collaboration between pharmacists and specialist medical doctors is essential in early identification of prodromal symptoms of cognitive impairment and AD. The Prompt detection of the condition in this group of patients allowed the specialists to recommend in-depth diagnostic tests and follow-up procedures to slow the course of the disease. This would give time to carry out adequate caregiver training. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, elderly, frail elderly, observational study

DOI: 10.3233/JAD-231295

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 145-150, 2024

Authors: Czuczwar, Stanisław J. | Kocki, Janusz | Miziak, Barbara | Bogucki, Jacek | Bogucka-Kocka, Anna | Pluta, Ryszard

Article Type: Research Article

Abstract: Background: Understanding the phenomena underlying the non-selective susceptibility to ischemia of pyramidal neurons in the CA3 is important from the point of view of elucidating the mechanisms of memory loss and the development of dementia. Objective: The aim of the study was to investigate changes in genes expression of amyloid precursor protein , its cleaving enzymes and tau protein in CA3 post-ischemia with survival of 12–24 months. Methods: We used an ischemic model of Alzheimer’s disease to study the above genes using an RT-PCR protocol. Results: The expression of the amyloid precursor protein …gene was above the control values at all times post-ischemia. The expression of the α-secretase gene also exceeded the control values post-ischemia. The expression of the β-secretase gene increased 12 and 24 months post-ischemia, and 18 months was below control values. Presenilin 1 and 2 genes expression was significantly elevated at all times post-ischemia. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months post-ischemia. Conclusions: The study suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid precursor protein. Additionally data indicate that brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a modified tau protein-dependent manner. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area post-ischemia. In addition expression of tau protein gene modification after brain ischemia is useful in identifying ischemic mechanisms occurring in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid precursor protein, brainischemia, CA3 area, genes, presenilin 1 and 2, α-secretase, β-secretase, tau protein

DOI: 10.3233/JAD-231333

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 151-161, 2024

Authors: Acharya, Nimish K. | Grossman, Henya C. | Clifford, Peter M. | Levin, Eli C. | Light, Kenneth R. | Choi, Hana | Swanson II, Randel L. | Kosciuk, Mary C. | Venkataraman, Venkat | Libon, David J. | Matzel, Louis D. | Nagele, Robert G.

Article Type: Research Article

Abstract: Background: Increased blood-brain barrier (BBB) permeability and amyloid-β (Aβ) peptides (especially Aβ1–42 ) (Aβ42 ) have been linked to Alzheimer’s disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood. Objective: To test the hypothesis that chronic extravasation of bloodborne Aβ42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model. Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble …monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aβ42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes. Results: Mice injected with both PT and Aβ42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aβ42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aβ42 in animals injected with both PT and Aβ42 compared to controls. Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aβ42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD. Show more

Keywords: Aβ42, Alzheimer’s disease, amyloid-beta peptides, amyloid plaques, autoantibodies, blood-brain barrier, dementia, immunoglobulin G

DOI: 10.3233/JAD-231028

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 163-186, 2024

Authors: Vaishnav, Neil | Gonzalez, Rosa | Karunungan, Krystal | Tyler, Ana | Zheng, William | Arias, Jalayne J.

Article Type: Research Article

Abstract: Background: Documentation of preclinical biomarker tests for Alzheimer’s disease (AD) in the medical record may expose patients to employment and insurance discrimination risks. There is a gap in research describing clinicians’ approaches to documenting biomarker results. Objective: To evaluate discrimination risks faced by patients undergoing biomarker testing for AD through a qualitative analysis of clinician documentation practices. Methods: Semi-structured interviews using hypothetical patient scenarios. The qualitative analysis focused on interviewees’ responses related to documentation and disclosure of results. Results: We collected and analyzed 17 interviews with dementia experts; and identified three approaches to documenting …biomarkers as: an association with active AD, noninformative, and an increased susceptibility for AD. Those who associated biomarkers with active disease were more likely to favor disclosure to employers and insurers, which could increase discrimination risks. Conclusions: This study demonstrates the variety of documentation and disclosure practices likely to emerge for preclinical AD biomarker tests and highlights a need for guidelines in this area. Show more

Keywords: Alzheimer’s disease, biomarkers, legal liability, patient data privacy

DOI: 10.3233/JAD-230067

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 187-195, 2024

Authors: Kim, Sung-a | Maeda, Megumi | Murata, Fumiko | Fujii, Takayuki | Ueda, Emi | Ono, Rei | Fukuda, Haruhisa

Article Type: Research Article

Abstract: Background: The prevalence of Alzheimer’s disease (AD) is increasing in Japan due to population aging. The association between sensory impairment and incident AD remains unclear. Objective: This study aimed to investigate the impact of sensory impairment on incident AD. Methods: We analyzed residents of five municipalities participating in the Longevity Improvement & Fair Evidence (LIFE) Study. The participants comprised individuals who had newly applied for long-term care needs certification between 2017 and 2022 and had no cognitive impairment upon application or AD diagnosis within the preceding six months. Participants were classified according to sensory impairment status: …visual impairment (VI), hearing impairment (HI), neither sensory impairment (NSI), and dual sensory impairment (DSI). The month succeeding the certification application was set as the index month, and the interval from that month until AD onset was assessed. Multivariable Cox proportional hazards analysis was performed to calculate the risk of AD onset according to sensory impairment status while adjusting for sex, age, dependence level, self-reliance level, and comorbidities. Results: Among 14,186 participants, we identified 1,194 (8.4%) who developed AD over a median follow-up period of 22.6 months. VI and HI only were not associated with incident AD. However, DSI conferred a significantly higher risk (HR: 1.6, CI: 1.1–2.2, p  = 0.008) of AD onset than NSI. Conclusions: Individuals with concurrent DSI have a higher risk of developing AD than those with single or NSI. Preventing and treating sensory impairment may not only improve functional outcomes, but could also help to reduce the future risk of AD. Show more

Keywords: Alzheimer’s disease, cognition, cohort study, dementia, sensory impairment

DOI: 10.3233/JAD-230806

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 197-207, 2024

Authors: Sun, Haoqi | Li, Peng | Gao, Lei | Yang, Jingyun | Yu, Lei | Buchman, Aron S. | Bennett, David A. | Westover, M. Brandon | Hu, Kun

Article Type: Research Article

Abstract: Background: Fractal motor activity regulation (FMAR), characterized by self-similar temporal patterns in motor activity across timescales, is robust in healthy young humans but degrades with aging and in Alzheimer’s disease (AD). Objective: To determine the timescales where alterations of FMAR can best predict the clinical onset of AD. Methods: FMAR was assessed from actigraphy at baseline in 1,077 participants who had annual follow-up clinical assessments for up to 15 years. Survival analysis combined with deep learning (DeepSurv) was used to examine how baseline FMAR at different timescales from 3 minutes up to 6 hours contributed differently to the …risk for incident clinical AD. Results: Clinical AD occurred in 270 participants during the follow-up. DeepSurv identified three potential regions of timescales in which FMAR alterations were significantly linked to the risk for clinical AD: <10, 20–40, and 100–200 minutes. Confirmed by the Cox and random survival forest models, the effect of FMAR alterations in the timescale of <10 minutes was the strongest, after adjusting for covariates. Conclusions: Subtle changes in motor activity fluctuations predicted the clinical onset of AD, with the strongest association observed in activity fluctuations at timescales <10 minutes. These findings suggest that short actigraphy recordings may be used to assess the risk of AD. Show more

Keywords: Actigraphy, Alzheimer’s disease, deep learning, motor activity

DOI: 10.3233/JAD-230928

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 209-220, 2024

Authors: Rajabli, Farid | Seixas, Azizi A. | Akgun, Bilcag | Adams, Larry D. | Inciute, Jovita | Hamilton, Kara L. | Whithead, Patrice G. | Konidari, Ioanna | Gu, Tianjie | Arvizu, Jamie | Golightly, Charles G. | Starks, Takiyah D. | Laux, Renee | Byrd, Goldie S. | Haines, Jonathan L. | Beecham, Gary W. | Griswold, Anthony J. | Vance, Jeffery M. | Cuccaro, Michael L. | Pericak-Vance, Margaret A.

Article Type: Research Article

Abstract: Background: Cognitive and functional abilities in individuals with Alzheimer’s disease (AD) pathology (ADP) are highly variable. Factors contributing to this variability are not well understood. Previous research indicates that higher educational attainment (EA) correlates with reduced cognitive impairments among those with ADP. While cognitive and functional impairments are correlated, they are distinguishable in their manifestations. Objective: To investigate whether levels of education are associated with functional impairments among those with ADP. Methods: This research involved 410 African American (AA) individuals (Institutional Review Boards 20070307, 01/27/2023) to ascertain whether EA correlates with functional resilience and if this …effect varies between APOE ɛ4 carriers and non-carriers. Utilizing EA as a cognitive reserve proxy, CDR-FUNC as a functional difficulties measure, and blood pTau181 as an ADP proxy, the non-parametric Mann-Whitney U test assessed the relationship between EA and CDR-FUNC in individuals with advanced pTau181 levels. Results: The results showed that EA correlated with functional difficulties in AA individuals with high levels of pTau181, such that individuals with high EA are more likely to have better functional ability compared to those with lower EA (W  = 730.5, p  = 0.0007). Additionally, we found that the effect of high EA on functional resilience was stronger in ɛ4 non-carriers compared to ɛ4 carriers (W  = 555.5, p  = 0.022). Conclusion: This study extends the role of cognitive reserve and EA to functional performance showing that cognitive reserve influences the association between ADP burden and functional difficulties. Interestingly, this protective effect seems less pronounced in carriers of the strong genetic risk allele ɛ4. Show more

Keywords: Alzheimer’s disease, APOE, biomarker, education

DOI: 10.3233/JAD-231116

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 221-229, 2024

Authors: Nallapu, Bhargav T. | Petersen, Kellen K. | Lipton, Richard B. | Davatzikos, Christos | Ezzati, Ali

Article Type: Research Article

Abstract: Background: Blood-based biomarkers (BBMs) are of growing interest in the field of Alzheimer’s disease (AD) and related dementias. Objective: This study aimed to assess the ability of plasma biomarkers to 1) predict disease progression from mild cognitive impairment (MCI) to dementia and 2) improve the predictive ability of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) measures when combined. Methods: We used data from the Alzheimer’s Disease Neuroimaging Initiative. Machine learning models were trained using the data from participants who remained cognitively stable (CN-s) and with Dementia diagnosis at 2-year follow-up visit. The models were used …to predict progression to dementia in MCI individuals. We assessed the performance of models with plasma biomarkers against those with CSF and MRI measures, and also in combination with them. Results: Our models with plasma biomarkers classified CN-s individuals from AD with an AUC of 0.75±0.03 and could predict conversion to dementia in MCI individuals with an AUC of 0.64±0.03 (17.1% BP, base prevalence). Models with plasma biomarkers performed better when combined with CSF and MRI measures (CN versus AD: AUC of 0.89±0.02; MCI-to-AD: AUC of 0.76±0.03, 21.5% BP). Conclusions: Our results highlight the potential of plasma biomarkers in predicting conversion to dementia in MCI individuals. While plasma biomarkers could improve the predictive ability of CSF and MRI measures when combined, they also show the potential to predict non-progression to AD when considered alone. The predictive ability of plasma biomarkers is crucially linked to reducing the costly and effortful collection of CSF and MRI measures. Show more

Keywords: Alzheimer’s disease, dementia, disease progression, feature engineering, plasma biomarkers, predictive models

DOI: 10.3233/JAD-230620

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 231-246, 2024

Authors: Sabbir, Mohammad Golam

Article Type: Research Article

Abstract: Background: Loss of Cholinergic Receptor Muscarinic 1 (CHRM1) has been linked to the pathogenesis of Alzheimer’s disease (AD). Our recent study found significantly lower CHRM1 protein levels in AD patient cortices, linked to reduced survival. Furthermore, using knockout mice (Chrm1−/− ) we demonstrated that deletion of Chrm1 alters cortical mitochondrial structure and function, directly establishing a connection between its loss and mitochondrial dysfunction in the context of AD. While CHRM1’s role in the brain has been extensively investigated, its impact on peripheral neurons in AD remains a crucial area of research, especially considering reported declines in peripheral nerve conduction among …AD patients. Objective: The objective was to characterize Chrm1 localization and mitochondrial deficits in Chrm1−/− dorsal root ganglion (DRG) neurons. Methods: Recombinant proteins tagged with Green or Red Fluorescent Protein (GFP/RFP) were transiently expressed to investigate the localization of Chrm1 and mitochondria, as well as mitochondrial movement in the neurites of cultured primary mouse DRG neurons, using confocal time-lapse live cell imaging. Transmission electron microscopy was performed to examine the ultrastructure of mitochondria in both wild-type and Chrm1−/− DRGs. Results: Fluorescence imaging revealed colocalization and comigration of N-terminal GFP-tagged Chrm1 and mitochondrial localization signal peptide-tagged RFP-labelled mitochondria in the DRGs neurons. A spectrum of mitochondrial structural abnormalities, including disruption and loss of cristae was observed in 87% neurons in Chrm1−/− DRGs. Conclusions: This study suggests that Chrm1 may be localized in the neuronal mitochondria and loss of Chrm1 in peripheral neurons causes sever mitochondrial structural aberrations resembling AD pathology. Show more

Keywords: Alzheimer’s disease, Cholinergic Receptor Muscarinic 1, cristae, dorsal root ganglion neuron, endoplasmic reticulum, mitochondria, sensory neuron, transmission electron microscopy

DOI: 10.3233/JAD-230883

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 247-264, 2024

Authors: Alva, Gus | Cubała, Wiesław J. | Berrio, Ana | Coate, Bruce | Abler, Victor | Pathak, Sanjeev

Article Type: Research Article

Abstract: Background: Pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, is the only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Further expanding knowledge of the safety profile of pimavanserin in PDP and neurodegenerative diseases (NDD) such as Alzheimer’s disease is of great interest for informing its use in patients with PDP (with or without dementia), given this population is highly sensitive to adverse effects following antipsychotic use. Objective: This trial evaluated the effects of pimavanserin compared to placebo in frail older adults and elderly patients with neuropsychiatric symptoms related …to NDD, such as hallucinations and delusions, to better understand the safety of pimavanserin in this population. Methods: This was a phase 3b, 8-week treatment (study duration of up to 16 weeks), multicenter, randomized, double-blind, placebo-controlled, two-arm parallel-group trial (NCT03575052). The primary endpoint was safety and tolerability, measured by treatment-emergent adverse events (TEAEs). Secondary safety endpoints were change from baseline in motor and cognitive function; exploratory endpoints included suicidality, sleep quality, and neuropsychiatric symptoms. Results: Incidences of TEAEs were similar between treatment groups; 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%), and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%). Pimavanserin did not impact motor- or cognitive-related function. Conclusions: Pimavanserin was well tolerated and not associated with motor or cognitive impairment. Together, these findings highlight the manageable and generally favorable safety profile of pimavanserin in patients with NDD, contributing to our knowledge on the safety of pimavanserin as it generalizes to patients with PDP. Show more

Keywords: Alzheimer’s disease, elderly patients, neurodegenerative diseases, neuropsychiatric symptoms, pimavanserin, safety

DOI: 10.3233/JAD-231167

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 265-274, 2024

Authors: Matsuzono, Kosuke | Mashiko, Takafumi | Koide, Reiji | Yoshizumi, Hiroaki | Fujimoto, Shigeru

Article Type: Research Article

Abstract: Background: While many studies focus on the prognosis of individual neurological diseases, very few comprehensively compare and analyze real-world data of these diseases. Objective: To address this gap in knowledge, in this study, we comprehensively analyzed the real-life data of patients with neurological diseases. Methods: We prospectively enrolled patients with neurological diseases at three hospitals from December 1, 2016 to September 30, 2020. Neurological diseases were classified into nine groups: Dementia, Cerebrovascular disease, Parkinson’s and related, Functional, Spinocerebellar degeneration, Neuroimmune, Epilepsy, Muscle dystrophy disease, and Hypertension. Patients were followed up for three years, and their prognosis …and evaluation of their cognitive function served as the endpoint. Results: A total of 426 patients were finally enrolled. Both mortality and cognitive function differed among the neurological disease categories. After 3 years, mortality was highest in the Dementia (25.5%), Parkinson’s and related (21.6%), and Spinocerebellar degeneration (35.3%) groups while the cognitive function of patients in these three groups was significantly lowest. Conclusions: When the neurological diseases were holistically observed, both mortality and cognitive function of the Dementia, Parkinson’s and related, and Spinocerebellar degeneration groups were significantly worse than the remaining diseases. Show more

Keywords: Aging society, Alzheimer’s disease, dementia, geriatric medicine, relentless neurological disease, prognosis

DOI: 10.3233/JAD-231390

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 275-285, 2024

Authors: Torres-Atencio, Ivonne | Carreira, Maria B. | Méndez, Alondra | Quintero, Maryonelly | Broce, Adriana | Oviedo, Diana C. | Rangel, Giselle | Villarreal, Alcibiades E. | Tratner, Adam E. | Rodríguez-Araña, Sofía | Britton, Gabrielle B.

Article Type: Research Article

Abstract: Background: A growing body of evidence points to potential risks associated with polypharmacy (using ≥5 medications) in older adults, but most evidence is derived from studies where racial and ethnic minorities remain underrepresented among research participants. Objective: Investigate the association between polypharmacy and cognitive function, subjective health state, frailty, and falls in Hispanic older adults. Methods: Panama Aging Research Initiative–Health Disparities (PARI-HD) is a community-based cohort study of older adults free of dementia at baseline. Cognitive function was measured with a neuropsychological test battery. Frailty assessment was based on the Fried criteria. Subjective health state and …falls were self-reported. Linear and multinomial logistic regression analyses were used to examine association. Results: Baseline evaluations of 468 individuals with a mean age of 69.9 years (SD = 6.8) were included. The median number of medications was 2 (IQR: 1–4); the rate of polypharmacy was 19.7% (95% confidence interval [CI] = 16.1–23.3). Polypharmacy was inversely associated with self-rated overall health (b  =−5.89, p  < 0.01). Polypharmacy users had 2.3 times higher odds of reporting two or more falls in the previous 12 months (odds ratio [OR] = 2.31, 95% CI = 1.06–5.04). Polypharmacy was independently associated with Fried’s criteria for pre-frailty (OR = 2.90, 95% CI = 1.36–5.96) and frailty (OR = 5.14, 95% CI = 1.83–14.42). Polypharmacy was not associated with cognitive impairment. Conclusions: These findings illustrate the potential risks associated with polypharmacy among older adults in Panama and may inform interventions to improve health outcomes in this population. Show more

Keywords: Aging, Alzheimer’s disease, Central America, cognitive impairment, dementia, falls, frailty, Latin America, polypharmacy

DOI: 10.3233/JAD-231001

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 287-300, 2024

Authors: Culibrk, Robert A. | Ebbert, Katherine A. | Yeisley, Daniel J. | Chen, Rui | Qureshi, Fatir A. | Hahn, Juergen | Hahn, Mariah S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by disrupted proteostasis and macroautophagy (hereafter “autophagy”). The pharmacological agent suramin has known autophagy modulation properties with potential efficacy in mitigating AD neuronal pathology. Objective: In the present work, we investigate the impact of forebrain neuron exposure to suramin on the Akt/mTOR signaling pathway, a major regulator of autophagy, in comparison with rapamycin and chloroquine. We further investigate the effect of suramin on several AD-related biomarkers in sporadic AD (sAD)-derived forebrain neurons. Methods: Neurons differentiated from ReNcell neural progenitors were used to assess the impact of suramin on the Akt/mTOR …signaling pathway relative to the autophagy inducer rapamycin and autophagy inhibitor chloroquine. Mature forebrain neurons were differentiated from induced pluripotent stem cells (iPSCs) sourced from a late-onset sAD patient and treated with 100μM suramin for 72 h, followed by assessments for amyloid-β, phosphorylated tau, oxidative/nitrosative stress, and synaptic puncta density. Results: Suramin treatment of sAD-derived neurons partially ameliorated the increased p-Tau(S199)/Tau ratio, and fully remediated the increased glutathione to oxidized nitric oxide ratio, observed in untreated sAD-derived neurons relative to healthy controls. These positive results may be due in part to the distinct increases in Akt/mTOR pathway mediator p-p70S6K noted with suramin treatment of both ReNcell-derived and iPSC-derived neurons. Longer term neuronal markers, such as synaptic puncta density, were unaffected by suramin treatment. Conclusions: These findings provide initial evidence supporting the potential of suramin to reduce the degree of dysregulation in sAD-derived forebrain neurons in part via the modulation of autophagy. Show more

Keywords: Alzheimer’s disease, autophagy, induced pluripotent stem cells, neurons, suramin

DOI: 10.3233/JAD-230600

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 301-318, 2024

Authors: Nester, Caroline O. | Gao, Qi | Katz, Mindy J. | Mogle, Jacqueline A. | Wang, Cuiling | Derby, Carol A. | Lipton, Richard B. | Saykin, Andrew J. | Rabin, Laura A.

Article Type: Research Article

Abstract: Background: The Cognitive Change Index (CCI) is a widely-used measure of self-perceived cognitive ability and change. Unfortunately, it is unclear if the CCI predicts future cognitive and clinical decline. Objective: We evaluated baseline CCI to predict transition from normal cognition to cognitive impairment in nondemented older adults and in predementia groups including, subjective cognitive decline, motoric cognitive risk syndrome, and mild cognitive impairment. Different versions of the CCI were assessed to uncover any differential risk sensitivity. We also examined the effect of ethnicity/race on CCI. Methods: Einstein Aging Study participants (N  = 322, Mage  = 77.57±4.96, % female=67.1, …Meducation  = 15.06±3.54, % non-Hispanic white = 46.3) completed an expanded 40-item CCI version (CCI-40) and neuropsychological evaluation (including Clinical Dementia Rating Scale [CDR], Montreal Cognitive Assessment, and Craft Story) at baseline and annual follow-up (Mfollow - up =3.4 years). CCI-40 includes the original 20 items (CCI-20) and the first 12 memory items (CCI-12). Linear mixed effects models (LME) and generalized LME assessed the association of CCI total scores at baseline with rate of decline in neuropsychological tests and CDR. Results: In the overall sample and across predementia groups, the CCI was associated with rate of change in log odds on CDR, with higher CCI at baseline predicting faster increase in the odds of being impaired on CDR. The predictive validity of the CCI broadly held across versions (CCI-12, 20, 40) and ethnic/racial groups (non-Hispanic black and white). Conclusions: Self-perception of cognitive change on the CCI is a useful marker of dementia risk in demographically/clinically diverse nondemented samples. All CCI versions successfully predicted decline. Show more

Keywords: Alzheimer’s disease, cognitive change index, ethnic/racial minoritized groups, mild cognitive impairment, motoric cognitive risk syndrome, non-Hispanic Black older adults, normal aging, subjective cognitive decline

DOI: 10.3233/JAD-230752

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 319-332, 2024

Authors: Cogram, Patricia | Garduño, B. Maximiliano | Ren, Bing | Xu, Xiangmin

Article Type: Meeting Report

Abstract: The first International Conference on Unconventional Animal Models of Alzheimer’s Disease and Aging (UAMAA) took place on December 13–16, 2023, in Santiago, Chile. The Alzheimer’s disease (AD) research field is currently in search for new and unconventional models that could hold greater translational potential than transgenic mouse models. Thus this UAMAA conference is timely and significant. The event consisted of 6 sessions with talks from 28 world-class scientists from all over the world. These animal models of interest include the degu (Octodon degu ), the dog (Canis familiaris ), and certain species of nonhuman primates that may better recapitulate neuropathology …and cognitive impairments in human AD. Our conference has provided a formal forum to discuss and highlight new research directions, alternative animal models, and innovative approaches for the AD and aging research field. Show more

Keywords: Aging, Alzheimer’s disease, animal model, Chile, conference, degu, dog, marmoset, meeting report

DOI: 10.3233/JAD-249004

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 333-336, 2024

Authors: Perry, George

Article Type: Book Review

DOI: 10.3233/JAD-249002

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 337-337, 2024

Article Type: Retraction

DOI: 10.3233/JAD-239015

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 339-339, 2024

Article Type: Retraction

DOI: 10.3233/JAD-239016

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 341-341, 2024