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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Seltmann, Henriette | Teichmann, Birgit
Article Type: Research Article
Abstract: Background: The number of people with dementia (PwD) in acute care hospitals is steadily increasing, posing a challenge for those who work closely with patients. To date, no German study has addressed the extent to which prospective nurses benefit from dementia training in terms of their knowledge, attitudes, and confidence in caring for PwD. Objective: The aim of this study is to investigate whether a validated dementia training for registered nurses can positively change nursing students’ knowledge about dementia, their attitude toward PwD, and their confidence in caring for them, as well as the stability over …time. Methods: In the one-group pre-test, post-test design, a sample of 81 nursing students was recruited from two nursing schools in Germany between May and June 2023. They completed a questionnaire consisting of the Dementia Knowledge Assessment Scale, the Dementia Attitude Scale, and the Confidence in Dementia Scale, as well as sociodemographic questions and experiences with PwD at three measurement points. The data were analyzed using the Wilcoxon test and repeated measures ANOVA. Results: The training has a significant effect on knowledge in dementia (z = –5.07, p < 0.001), attitude toward PwD (z = –4.42, p < 0.001), and confidence in caring for them at the post-test (z = –3. 21, p < 0.001, r = 0.36). The repeated measures ANOVA shows stability over time only for dementia knowledge. Conclusions: The results indicate the need for further research in this field as well as the validation of the dementia training specifically addressing nursing students. Show more
Keywords: Alzheimer’s disease, attitude, communication, confidence, dementia, intervention, knowledge, nursing students
DOI: 10.3233/JAD-231338
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Mandal, Pravat K.
Article Type: Editorial
DOI: 10.3233/JAD-240217
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Zhong, Ping | Cao, Qing | Yan, Zhen
Article Type: Research Article
Abstract: Background: The impairment of neural circuits controlling cognitive processes has been implicated in the pathophysiology of Alzheimer’s disease and related disorders (ADRD). However, it is largely unclear what circuits are specifically changed in ADRD, particularly at the early stage. Objective: Our goal of this study is to reveal the functional changes in the circuit of entorhinal cortex (EC), an interface between neocortex and hippocampus, in AD. Methods: Electrophysiological, optogenetic and chemogenetic approaches were used to examine and manipulate entorhinal cortical circuits in amyloid-β familial AD model (5×FAD) and tauopathy model (P301S Tau). Results: We …found that, compared to wild-type mice, electrical stimulation of EC induced markedly smaller responses in subiculum (hippocampal output) of 5×FAD mice (6-month-old), suggesting that synaptic communication in the EC to subiculum circuit is specifically blocked in this AD model. In addition, optogenetic stimulation of glutamatergic terminals from prefrontal cortex (PFC) induced smaller responses in EC of 5×FAD and P301S Tau mice (6-month-old), suggesting that synaptic communication in the PFC to EC pathway is compromised in both ADRD models. Chemogenetic activation of PFC to EC pathway did not affect the bursting activity of EC neurons in 5×FAD mice, but partially restored the diminished EC neuronal activity in P301S Tau mice. Conclusions: These data suggest that 5×FAD mice has a specific impairment of short-range hippocampal gateway (EC to subiculum), which may be caused by amyloid-β deposits; while two ADRD models have a common impairment of long-range cortical to hippocampal circuit (PFC to EC), which may be caused by microtubule/tau-based transport deficits. These circuit deficits provide a pathophysiological basis for unique and common impairments of various cognitive processes in ADRD conditions. Show more
Keywords: Alzheimer’s disease, electrophysiology, entorhinal cortex, 5×FAD, neural circuits, optogenetics, P301S Tau, prefrontal cortex, subiculum
DOI: 10.3233/JAD-231413
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Zhang, Xueyi | Gomez, Lissette | Below, Jennifer E. | Naj, Adam C. | Martin, Eden R. | Kunkle, Brian W. | Bush, William S.
Article Type: Research Article
Abstract: Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer’s disease (AD). Objective: To model the expression of X chromosome genes and evaluate their impact on AD risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF > 0.05) within the cis -regulatory window were used to train tissue-specific models of each gene. …We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer’s Disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p < 0.05, with only ARMCX6 in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6 . Show more
Keywords: Alzheimer’s disease, bioinformatics, elastic net regression, gene expression, gene prediction, sex differences, transcriptome, X chromosome
DOI: 10.3233/JAD-231075
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Papadimitriou, Amelia | Dawson, Aprill Z. | Thorgerson, Abigail | Bhandari, Sanjay | Martinez, Martin | Egede, Leonard E.
Article Type: Research Article
Abstract: Background: The prevalence of type 2 diabetes is increasing with the burden disproportionately falling on older adults and racial/ethnic minorities. Older adults with diabetes show greater cognitive decline and there are disparities in cognitive function by race/ethnicity that can be explained by social determinants such as wealth. Objective: To understand whether there is a differential relationship between wealth and cognitive function by race/ethnicity among older U.S. adults with diabetes. Methods: Data on 9,006 adults aged 50+ with diabetes from the Health and Retirement Study (2006–2016) were analyzed. The primary outcome, cognitive function, was a score ranging …from range 0–27 categorized as: normal [12–27], mild cognitive impairment (MCI) [7–11], and dementia including Alzheimer’s disease [0–6]. Three modeled outcomes were: 1) normal versus MCI, 2) normal versus dementia, 3) MCI versus dementia. Wealth was log transformed and used as continuous and binary (≥median, <median). Logistic generalized estimating equation models were used to examine the relationship between wealth and cognitive function and models were stratified by race/ethnicity. Models were adjusted for demographics, lifestyle, functional limitations, and comorbidities. Results: In adjusted models, greater wealth was significantly associated with lower odds of MCI and dementia for all groups. Similarly, having wealth less than the sample median was associated with higher odds of MCI and dementia compared to wealth≥sample median. Conclusions: Increased wealth was significantly protective against MCI and dementia for all ethnic groups. Wealth less than the sample median was associated with greater odds of dementia for NHB and NHW. Show more
Keywords: Alzheimer’s disease, cognitive function, dementia, diabetes, mild cognitive impairment, older adults, racial/ethnic disparities, wealth
DOI: 10.3233/JAD-231107
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Cabrera-León, Ylermi | Báez, Patricio García | Fernández-López, Pablo | Suárez-Araujo, Carmen Paz
Article Type: Systematic Review
Abstract: Background: The growing number of older adults in recent decades has led to more prevalent geriatric diseases, such as strokes and dementia. Therefore, Alzheimer’s disease (AD), as the most common type of dementia, has become more frequent too. Background: Objective: The goals of this work are to present state-of-the-art studies focused on the automatic diagnosis and prognosis of AD and its early stages, mainly mild cognitive impairment, and predicting how the research on this topic may change in the future. Methods: Articles found in the existing literature needed to fulfill …several selection criteria. Among others, their classification methods were based on artificial neural networks (ANNs), including deep learning, and data not from brain signals or neuroimaging techniques were used. Considering our selection criteria, 42 articles published in the last decade were finally selected. Results: The most medically significant results are shown. Similar quantities of articles based on shallow and deep ANNs were found. Recurrent neural networks and transformers were common with speech or in longitudinal studies. Convolutional neural networks (CNNs) were popular with gait or combined with others in modular approaches. Above one third of the cross-sectional studies utilized multimodal data. Non-public datasets were frequently used in cross-sectional studies, whereas the opposite in longitudinal ones. The most popular databases were indicated, which will be helpful for future researchers in this field. Conclusions: The introduction of CNNs in the last decade and their superb results with neuroimaging data did not negatively affect the usage of other modalities. In fact, new ones emerged. Show more
Keywords: Alzheimer’s disease, blood, computer-assisted diagnosis, deep learning, gait, genes, mild cognitive impairment, neural networks (computer), neuropsychological tests, speech
DOI: 10.3233/JAD-231271
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-31, 2024
Authors: Aljassabi, Ali | Zieneldien, Tarek | Kim, Janice | Regmi, Deepika | Cao, Chuanhai
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is an extremely complex and heterogeneous pathology influenced by many factors contributing to its onset and progression, including aging, amyloid-beta (Aβ) plaques, tau fibril accumulation, inflammation, etc. Despite promising advances in drug development, there is no cure for AD. Although there have been substantial advancements in understanding the pathogenesis of AD, there have been over 200 unsuccessful clinical trials in the past decade. In recent years, immunotherapies have been at the forefront of these efforts. Immunotherapy alludes to the immunological field that strives to identify disease treatments via the enhancement, suppression, or induction of immune responses. Interestingly, …immunotherapy in AD is a relatively new approach for non-infectious disease. At present, antibody therapy (passive immunotherapy) that targets anti-Aβ aimed to prevent the fibrillization of Aβ peptides and disrupt pre-existing fibrils is a predominant AD immunotherapy due to the continuous failure of active immunotherapy for AD. The most rational and safe strategies will be those targeting the toxic molecule without triggering an abnormal immune response, offering therapeutic advantages, thus making clinical trial design more efficient. This review offers a concise overview of immunotherapeutic strategies, including active and passive immunotherapy for AD. Our review encompasses approved methods and those presently under investigation in clinical trials, while elucidating the recent challenges, complications, successes, and potential treatments. Thus, immunotherapies targeting Aβ throughout the disease progression using a mutant oligomer-Aβ stimulated dendritic cell vaccine may offer a promising therapy in AD. Show more
Keywords: Alzheimer’s disease, amyloid-β , dendritic cell, immunotherapies, vaccine
DOI: 10.3233/JAD-231163
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Martínez-Dubarbie, Francisco | López-García, Sara | Lage, Carmen | Di Molfetta, Guglielmo | Fernández-Matarrubia, Marta | Pozueta-Cantudo, Ana | García-Martínez, María | Corrales-Pardo, Andrea | Bravo, María | Jiménez-Bonilla, Julio | Quirce, Remedios | Marco de Lucas, Enrique | Drake-Pérez, Marta | Tordesillas, Diana | López-Hoyos, Marcos | Irure-Ventura, Juan | Valeriano-Lorenzo, Elizabeth | Blennow, Kaj | Ashton, Nicholas J. | Zetterberg, Henrik | Rodríguez-Rodríguez, Eloy | Sánchez-Juan, Pascual
Article Type: Research Article
Abstract: Background: Plasma biomarkers of Alzheimer’s disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We …also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid. Show more
Keywords: Alzheimer’s disease, longitudinal study, p-tau231, plasma biomarkers, presymptomatic stages
DOI: 10.3233/JAD-231479
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Podger, Lauren | Stewart, Walter F. | Serrano, Daniel | Lipton, Richard B. | Gomez-Ulloa, David | Ayasse, Nicolai D. | Barnes, Frederick B. | Davis, E. Anne | Runken, M. Chris
Article Type: Research Article
Abstract: Background: A theoretical endpoint staging framework was previously developed and published, aligning outcomes (i.e., memory) to the stage of Alzheimer’s disease (AD) in which a given outcome is most relevant (i.e., has the greatest risk of degradation). The framework guides the selection of endpoints measuring outcomes relevant within a target AD population. Here, a proof of concept is presented via post-hoc analyses of the Alzheimer Management by Albumin Replacement (AMBAR) Phase 2b clinical trial in patients with AD (NCT01561053, 2012). Objective: To evaluate whether aligning endpoints measuring cognition, function, and quality of life to hypothesized ‘target’ stages …of AD yields magnitudes of treatment efficacy greater than those reported in the AMBAR full analysis set (FAS). Methods: Three endpoints were tested: ADAS-Cog 12, ADCS-ADL, and QoL-AD. The magnitude of treatment efficacy was hypothesized to be maximized in the target stages of mild, mild-to-moderate, and very mild AD, respectively, compared to the full analysis set (FAS) and non-target stages. Results: For ADAS-Cog 12, the magnitude of treatment efficacy was largest in the non-target stage (–4.0, p = 0.0760) compared to target stage and FAS. For ADCS-ADL and QoL-AD, the magnitude of treatment efficacy was largest in the target stage (14.2, p = 0.0003; 2.4, p < 0.0001, respectively) compared to non-target stage and FAS. Conclusions: Findings indicated that evaluating endpoints in the most relevant AD stage can increase the magnitude of the observed treatment efficacy. Evidence provides preliminary proof of concept for the endpoint staging framework. Show more
Keywords: Alzheimer’s disease, AMBAR, cognition, endpoint staging framework, function, outcome measures, quality of life, trial endpoints
DOI: 10.3233/JAD-231197
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: O’Shea, Deirdre M. | Camacho, Simone | Ezzeddine, Reem | Besser, Lilah | Tolea, Magdalena I. | Wang, Lily | Galvin, Conor | Gibbs, Gregory | Galvin, James E.
Article Type: Research Article
Abstract: Background: Lifestyle factors are linked to differences in brain aging and risk for Alzheimer’s disease, underscored by concepts like ‘cognitive reserve’ and ‘brain maintenance’. The Resilience Index (RI), a composite of 6 factors (cognitive reserve, physical and cognitive activities, social engagement, diet, and mindfulness) provides such a holistic measure. Objective: This study aims to examine the association of RI scores with cognitive function and assess the mediating role of cortical atrophy. Methods: Baseline data from 113 participants (aged 45+, 68% female) from the Healthy Brain Initiative were included. Life course resilience was estimated with the RI, …cognitive performance with Cognivue® , and brain health using a machine learning derived Cortical Atrophy Score (CAS). Mediation analysis probed the relationship between RI, cognitive outcomes, and cortical atrophy. Results: In age and sex adjusted models, the RI was significantly associated with CAS (β= –0.25, p = 0.006) and Cognivue® scores (β= 0.32, p < 0.001). The RI-Cognivue® association was partially mediated by CAS (β= 0.07; 95% CI [0.02, 0.14]). Conclusions: Findings revealed that the collective effect of early and late-life lifestyle resilience factors on cognition are partially explained by their association with less brain atrophy. These findings underscore the value of comprehensive lifestyle assessments in understanding the risk and progression of cognitive decline and Alzheimer’s disease in an aging population. Show more
Keywords: Alzheimer’s disease, cognitive reserve, cognitive resilience, cortical atrophy, mild cognitive impairment
DOI: 10.3233/JAD-231346
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
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