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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
Authors: Soares Martins, Tânia | Ferreira, Maria | Magalhães, Sandra | Leandro, Kevin | Almeida, Luís P. de | Vogelgsang, Jonathan | Breitling, Benedict | Hansen, Niels | Esselmann, Hermann | Wiltfang, Jens | da Cruz e Silva, Odete A.B. | Nunes, Alexandra | Henriques, Ana Gabriela
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) diagnosis is difficult, and new accurate tools based on peripheral biofluids are urgently needed. Extracellular vesicles (EVs) emerged as a valuable source of biomarker profiles for AD, since their cargo is disease-specific and these can be easily isolated from easily accessible biofluids, as blood. Fourier Transform Infrared (FTIR) spectroscopy can be employed to analyze EVs and obtain the spectroscopic profiles from different regions of the spectra, simultaneously characterizing carbohydrates, nucleic acids, proteins, and lipids. Objective: The aim of this study was to identify blood-derived EVs (bdEVs) spectroscopic signatures with AD discriminatory potential. …Methods: Herein, FTIR spectra of bdEVs from two biofluids (serum and plasma) and distinct sets of Controls and AD cases were acquired, and EVs’ spectra analyzed. Results: Analysis of bdEVs second derivative peaks area revealed differences between Controls and AD cases in distinct spectra regions, assigned to carbohydrates and nucleic acids, amides, and lipids. Conclusions: EVs’ spectroscopic profiles presented AD discriminatory value, supporting the use of bdEVs combined with FTIR as a screening or complementary tool for AD diagnosis. Show more
Keywords: Alzheimer’s disease, biomarker, diagnosis, extracellular vesicles, lipids, nucleic acids, proteins
DOI: 10.3233/JAD-231239
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Ramadan, Ferris A. | Arani, Gayatri | Jafri, Ayan | Thompson, Tingting | Bland, Victoria L. | Renquist, Benjamin | Raichlen, David A. | Alexander, Gene E. | Klimentidis, Yann C.
Article Type: Research Article
Abstract: Background: Late-onset Alzheimer’s disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted …glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD. Show more
Keywords: Alzheimer’s disease, glutamine, Mendelian randomization, metabolites
DOI: 10.3233/JAD-231063
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Shen, Zhiwei | Yang, Xinyi | Lan, Yulong | Chen, Gao
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and cognitive impairment due to excessive accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. Although decades of research efforts have been put into developing disease-modifying therapies for AD, no “curative” drug has been identified. As a central player in neuro-inflammation, microglia play a key role inbrain homeostasis by phagocytosing debris and regulating the balance between neurotoxic and neuroprotective events. Typically, the neurotoxic phenotype of activated microglia is predominant in the impaired microenvironment of AD. Accordingly, transitioning the activity state of microglia from pro-inflammatory to anti-inflammatory …can restore the disrupted homeostatic microenvironment. Recently, stem cell therapy holds great promise as a treatment for AD; however, the diminished survival of transplanted stem cells has resulted in a disappointing long-term outcome for this treatment. This article reviews the functional changes of microglia through the course of AD-associated homeostatic deterioration. We summarize the possible microglia-associated therapeutic targets including TREM2, IL-3Rα , CD22, C5aR1, CX3CR1, P2X7R, CD33, Nrf2, PPAR-γ , CSF1 R, and NLRP3, each of which has been discussed in detail. The goal of this review is to put forth the notion that microglia could be targeted by either small molecules or biologics to make the brain microenvironment more amenable to stem cell implantation and propose a novel treatment strategy for future stem cell interventions in AD. Show more
Keywords: Alzheimer’s disease, microenvironment, microglia, neuro-inflammation, stem cell
DOI: 10.3233/JAD-231159
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Sigurdsson, Einar M.
Article Type: Review Article
Abstract: The tau protein undergoes pathological changes in Alzheimer’s disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of …some antibodies targeting amyloid-β in Alzheimer’s disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer’s disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell. Show more
Keywords: Alzheimer’s disease, antibody, clinical trials, immunotherapy, tau protein, tauopathies, vaccine
DOI: 10.3233/JAD-231238
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Weinberg, Marc S. | He, Yingnan | Kivisäkk, Pia | Arnold, Steven E. | Das, Sudeshna
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a complicated condition involving multiple metabolic and immunologic pathophysiological processes that can occur with the hallmark pathologies of amyloid-β, tau, and neurodegeneration. Metformin, an anti-diabetes drug, targets several of these disease processes in in vitro and animal studies. However, the effects of metformin on human cerebrospinal fluid (CSF) and plasma proteins as potential biomarkers of treatment remain unexplored. Objective: Using proteomics data from a metformin clinical trial, identify the impact of metformin on plasma and CSF proteins. Methods: We analyzed plasma and CSF proteomics data collected previously …(ClinicalTrials.gov identifier: NCT01965756, conducted between 2013 and 2015), and conduced bioinformatics analyses to compare the plasma and CSF protein levels after 8 weeks of metformin or placebo use to their baseline levels in 20 non-diabetic patients with mild cognitive impairment (MCI) and positive AD biomarkers participants. Results: 50 proteins were significantly (unadjusted p < 0.05) altered in plasma and 26 in CSF after 8 weeks of metformin use, with 7 proteins in common (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A). The correlation between changes in plasma and CSF levels of these 7 proteins after metformin use relative to baseline levels was high (r = 0.98). The proteins also demonstrated temporal stability. Conclusions: Our pilot study is the first to investigate the effect of metformin on plasma and CSF proteins in non-diabetic patients with MCI and positive AD biomarkers and identifies several candidate plasma biomarkers for future clinical trials after confirmatory studies. Show more
Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, clinical trial, metformin, plasma
DOI: 10.3233/JAD-230899
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023
Authors: Hambali, Aqilah | Jusril, Nor Atiqah | Md Hashim, Nur Fariesha | Abd Manan, Nizar | Adam, Siti Khadijah | Mehat, Muhammad Zulfadli | Adenan, Mohd Ilham | Stanslas, Johnson | Abdul Hamid, Hafizah
Article Type: Research Article
Abstract: Background: Neuroinflammation and oxidative stress can aggravate the progression of Alzheimer’s disease (AD). Centella asiatica has been traditionally consumed for memory and cognition. The triterpenes (asiaticoside, madecassoside, asiatic acid, madecassic acid) have been standardized in the ethanolic extract of Centella asiatica (SECA). The bioactivity of the triterpenes in different solvent polarities of SECA is still unknown. Objective: In this study, the antioxidative and anti-neuroinflammatory effects of SECA and its fractions were explored on lipopolysaccharides (LPS)-induced microglial cells. Methods: HPLC measured the four triterpenes in SECA and its fractions. SECA and its fractions were tested …for cytotoxicity on microglial cells using MTT assay. NO, pro-inflammatory cytokines (TNF-α , IL-6, IL-1β), ROS, and MDA (lipid peroxidation) produced by LPS-induced microglial cells were measured by colorimetric assays and ELISA. Nrf2 and HO-1 protein expressions were measured using western blotting. Results: The SECA and its fractions were non-toxic to BV2 microglial cells at tested concentrations. The levels of NO, TNF-α , IL-6, ROS, and lipid peroxidation in LPS-induced BV2 microglial cells were significantly reduced (p < 0.001) by SECA and its fractions. SECA and some of its fractions can activate the Nrf2/HO-1 signaling pathway by significantly enhancing (p < 0.05) the Nrf2 and HO-1 protein expressions. Conclusions: This study suggests that the inhibitory activity of SECA and its fractions on pro-inflammatory and oxidative stress events may be the result of the activation of antioxidant defense systems. The potential of SECA and its fractions in reducing neuroinflammation and oxidative stress can be further studied as a potential therapeutic strategy for AD. Show more
Keywords: Alzheimer’s disease, Centella asiatica , HO-1, neuroinflammation, Nrf2, oxidative stress
DOI: 10.3233/JAD-230875
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Noori, Ayush | Jayakumar, Rojashree | Moturi, Vaishnavi | Li, Zhaozhi | Liu, Rongxin | Serrano-Pozo, Alberto | Hyman, Bradley T. | Das, Sudeshna
Article Type: Research Article
Abstract: Background: Recent Alzheimer’s disease (AD) discoveries are increasingly based on studies from a variety of omics technologies on large cohorts. Currently, there is no easily accessible resource for neuroscientists to browse, query, and visualize these complex datasets in a harmonized manner. Objective: Create an online portal of public omics datasets for AD research. Methods: We developed Alzheimer DataLENS, a web-based portal, using the R Shiny platform to query and visualize publicly available transcriptomics and genetics studies of AD on human cohorts. To ensure consistent representation of AD findings, all datasets were processed through a uniform bioinformatics …pipeline. Results: Alzheimer DataLENS currently houses 2 single-nucleus RNA sequencing datasets, over 30 bulk RNA sequencing datasets from 19 brain regions and 3 cohorts, and 2 genome-wide association studies (GWAS). Available visualizations for single-nucleus data include bubble plots, heatmaps, and UMAP plots; for bulk expression data include box plots and heatmaps; for pathways include protein-protein interaction network plots; and for GWAS results include Manhattan plots. Alzheimer DataLENS also links to two other knowledge resources: the AD Progression Atlas and the Astrocyte Atlas. Conclusions: Alzheimer DataLENS is a valuable resource for investigators to quickly and systematically explore omics datasets and is freely accessible at https://alzdatalens.partners.org . Show more
Keywords: Alzheimer’s disease, database, genetics, multiomics, single-cell RNA-seq, transcriptomics
DOI: 10.3233/JAD-230884
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Wang, Yongchun | Jiang, Richeng | Li, Mingxi | Wang, Zicheng | Yang, Yu | Sun, Li
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia, causing a huge socioeconomic burden. In parallel with the widespread uptake of single-cell RNA sequencing (scRNA-seq) technology, there has been a rapid accumulation of data produced by researching AD at single-cell resolution, which is more conductive to explore the neuroimmune-related mechanism of AD. Objective: To explore the potential features of T cells in the peripheral blood and cerebrospinal fluid of AD patients. Methods: Two datasets, GSE181279 and GSE134578, were integrated from GEO database. Seurat, Monocle, CellChat, scRepertoire, and singleR packages were mainly …employed for data analysis. Results: Our analysis demonstrated that in peripheral blood, T cells were significantly expanded, and these expanded T cells were possessed effector function, such as CD8+ TEMRA , CD4+ TEMRA , and CD8+ TEM . Interestingly, CD8+ TEMRA and CD4+ TEMRA cells positioned adjacently after dimensions reduction and clustering. Notably, we identified that the expanded T cells were developed from Naïve T cells and TCM cells, and TEM cells was in the intermediate state of this developing process. Additionally, in cerebrospinal fluid of AD patients, the amplified T cells were mainly CD8+ TEMRA cells, and the number and strength of communication between CD4+ TEM , CD8+ TEM , and CD8+ TEMRA were decreased in AD patients. Conclusions: Our comprehensive analyses identified the cells in cerebrospinal fluid from AD patients are expanded TEMRA or TEM cells and the TEMRA cells communicating with other immune cells is weakened, which may be an important immune feature that leads to AD. Show more
Keywords: Alzheimer’s disease, analysis of immune characteristics, immune cell subpopulation, single-cell RNA sequencing, TCR repertoire
DOI: 10.3233/JAD-230784
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023
Authors: Snytnikova, Olga | Telegina, Darya | Savina, Ekaterina | Tsentalovich, Yuri | Kolosova, Nataliya
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia in the elderly. Incomplete knowledge about the pathogenesis of this disease determines the absence of medications for the treatment of AD today. Animal models can provide the necessary knowledge to understand the mechanisms of biochemical processes occurring in the body in health and disease. Objective: To identify the most promising metabolomic predictors and biomarkers reflecting metabolic disorders in the development of AD signs. Methods: High resolution 1 H NMR spectroscopy was used for quantitative metabolomic profiling of the hippocampus of OXYS rats, an animal model …of sporadic AD, which demonstrates key characteristics of this disease. Animals were examined during several key periods: 20 days group corresponds to the “preclinical” period preceding the development of AD signs, during their manifestation (3 months), and active progression (18 months). Wistar rats of the same age were used as control. Results: Ranges of variation and mean concentrations were established for 59 brain metabolites. The main metabolic patterns during aging, which are involved in energy metabolism pathways and metabolic shifts of neurotransmitters, have been established. Of particular note is the significant increase of scyllo-inositol and decrease of hypotaurine in the hippocampus of OXYS rats as compared to Wistars for all studied age groups. Conclusions: We suggest that the accumulation of scyllo-inositol and the reduction of hypotaurine in the brain, even at an early age, can be considered as predictors and potential biomarkers of the development of AD signs in OXYS rats and, probably, in humans. Show more
Keywords: Aging, Alzheimer’s disease, hippocampal metabolome, hypotaurine, nuclear magnetic resonance spectroscopy, OXYS rats, scyllo-inositol
DOI: 10.3233/JAD-230706
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2023
Authors: Syed, Rafay Ali | Hayat, Mahnoor | Qaiser, Hammad | Uzair, Mohammad | Al-Regaiey, Khalid | Khallaf, Roaa | Kaleem, Imdad | Bashir, Shahid
Article Type: Review Article
Abstract: Aging is an intrinsic aspect of an organism’s life cycle and is characterized by progressive physiological decline and increased susceptibility to mortality. Many age-associated disorders, including neurological disorders, are most commonly linked with the aging process, such as Alzheimer’s disease (AD). This review aims to provide a comprehensive overview of the effects of aging and AD on the molecular pathways and levels of different proteins in the brain, including metalloproteins, neurotrophic factors, amyloid proteins, and tau proteins. AD is caused by the aggregation of amyloid proteins in the brain. Factors such as metal ions, protein ligands, and the oligomerization state …of amyloid precursor protein significantly influence the proteolytic processing of amyloid-β protein precursor (AβPP). Tau, a disordered cytosolic protein, serves as the principal microtubule-associated protein in mature neurons. AD patients exhibit decreased levels of nerve growth factor within their nervous systems and cerebrospinal fluid. Furthermore, a significant increase in brain-derived neurotrophic factor resulting from the neuroprotective effect of glial cell line-derived neurotrophic factor suggests that the synergistic action of these proteins plays a role in inhibiting neuronal degeneration and atrophy. The mechanism through which Aβ and AβPP govern Cu2+ transport and their influence on Cu2+ and other metal ion pools requires elucidation in future studies. A comprehensive understanding of the influence of aging and AD on molecular pathways and varying protein levels may hold the potential for the development of novel diagnostic and therapeutic methods for the treatment of AD. Show more
Keywords: Alzheimer’s disease, apoptosis, brain-derived neurotrophic factor, neurotrophic factors, oxidative stress
DOI: 10.3233/JAD-230801
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Jehu, Deborah A. | Pottayil, Faheem | Dong, Yanbin | Zhu, Haidong | Sams, Richard | Young, Lufei
Article Type: Research Article
Abstract: Background: Physical activity preserves cognitive function in people without dementia, but the relationship between physical activity and cognitive domains among people living with dementia is unclear. Objective: The objective of this study was to explore the association between physical activity and cognition domains among people living with dementia. Methods: Participants living with dementia in residential care facilities (complete case analysis: n = 24/42) completed a battery of cognitive tests (global cognition : Montreal Cognitive Assessment; executive function : Trail-Making Test, Digit Span Forward Test; perception and orientation : Benton Judgement of Line Orientation Test; …language : Boston Naming Test; learning and memory : Rey Auditory Verbal Learning Test; complex attention : Digit Symbol Substitution Test). Participants wore an actigraphy monitor on their non-dominant wrist over seven days. We conducted a linear regression for total physical activity (independent variable) with race (white/black), fall risk (Morse Fall Scale), and the number of comorbidities (Functional Comorbidities Index) as covariates, and cognitive tests as variables of interest. Results: Participants were primarily male (75%), white (87.5%), and 50%had unspecified dementia (Alzheimer’s disease: 33%). Greater physical activity was associated with poorer global cognition, better executive function, and better learning and memory (p s < 0.05). Physical activity was not related to visuospatial perception, language, or complex attention. Conclusions: Physical activity may preserve executive function and learning and memory among people living with dementia. Wandering is more common in later stages of dementia, which may explain greater physical activity observed with lower global cognition. Regularly assessing physical activity may be useful in screening and monitoring cognitive changes. Show more
Keywords: Accelerometry, actigraphy, Alzheimer’s disease, cognition, cognitive domains, dementia, physical activity
DOI: 10.3233/JAD-230594
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Carr, Rachel H. | Eom, Gina D. | Brown, Eric E.
Article Type: Systematic Review
Abstract: Background: Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental condition now recognized to persist into older adulthood, has been postulated to be a risk factor for neurocognitive disorders given the overlap in clinical features and neurobiology, as well as the complex interplay between ADHD and known risk factors for dementia. Studies have emerged assessing this relationship, but there has not yet been a comprehensive systematic review addressing this topic. Objective: To assess whether ADHD is a risk factor for neurocognitive disorders and to explore possible mechanisms for such an association. Methods: A systematic review of …the literature was conducted using Medline, Embase, and PsycINFO from inception until June 4, 2023. Studies were included if they assessed whether or how ADHD may be a risk factor for neurocognitive disorders. Studies were excluded if they were not primary literature, not published in a peer-reviewed journal, not in English, and/or used non-human subjects. Study quality was assessed using the QualSyst tool. Results: Sixteen studies met inclusion criteria. Seven studies found a positive association between ADHD and neurocognitive disorders (all-cause dementia in four studies, Alzheimer’s disease in three studies, Lewy body dementia in two studies, and mild cognitive impairment in one study). Four studies did not find an association. Five studies pertained to possible mechanisms for an association, including genetics, with minimal significant findings. Conclusions: ADHD may be a risk factor for certain neurocognitive disorders, although the evidence base is limited, and the absolute risk is small. Possible explanations include genetic and lifestyle factors. Show more
Keywords: Aged, Alzheimer’s disease, attention deficit disorder with hyperactivity, cognitive dysfunction, dementia, Lewy body disease, systematic review
DOI: 10.3233/JAD-230904
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Cao, Jing | Tang, Yating | Chen, Shujian | Yu, Siqi | Wan, Ke | Yin, Wenwen | Zhen, Wenhui | Zhao, Wenming | Zhou, Xia | Zhu, Xiaoqun | Sun, Zhongwu
Article Type: Research Article
Abstract: Background: The hippocampus consists of histologically and functionally distinct subfields, which shows differential vulnerabilities to Alzheimer’s disease (AD)-associated pathological changes. Objective: To investigate the atrophy patterns of the main hippocampal subfields in patients with mild cognitive impairment (MCI) and AD and the relationships among the hippocampal subfield volumes, plasma biomarkers and cognitive performance. Methods: This cross-sectional study included 119 patients stratified into three categories: normal cognition (CN; N = 40), MCI (N = 39), and AD (N = 40). AD-related plasma biomarkers were measured, including amyloid-β (Aβ)42 , Aβ 40 , Aβ 42 /Aβ 40 …ratio, p-tau181, and p-tau217, and the hippocampal subfield volumes were calculated using automated segmentation and volumetric procedures implemented in FreeSurfer. Results: The subiculum body, cornu ammonis (CA) 1-head, CA1-body, CA4-body, molecular_layer_HP-head, molecular_layer_HP-body, and GC-ML-DG-body volumes were smaller in the MCI group than in the CN group. The subiculum body and CA1-body volumes accurately distinguished MCI from CN (area under the curve [AUC] = 0.647–0.657). The subiculum-body, GC-ML-DG-body, CA4-body, and molecular_layer_HP-body volumes accurately distinguished AD from MCI (AUC = 0.822–0.833) and AD from CN (AUC = 0.903–0.905). The p-tau 217 level served as the best plasma indicator of AD and correlated with broader hippocampal subfield volumes. Moreover, mediation analysis demonstrated that the subiculum-body volume mediated the associations between the p-tau217 and p-tau181 levels, and the Montreal Cognitive Assessment and Auditory Verbal Learning Test recognition scores. Conclusions: Hippocampal subfields with distinctive atrophy patterns may mediate the effects of tau pathology on cognitive function. The subiculum-body may be the most clinically meaningful hippocampal subfield, which could be an effective target region for assessing disease progression. Show more
Keywords: Alzheimer’s disease, cognitive performance, hippocampal subfield volumes, mild cognitive impairment, plasma biomarkers
DOI: 10.3233/JAD-231114
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Zhai, Modi | Zhang, Yu | Yan, Dongxue | Wang, Yuzhen | Li, Wenzhong | Sun, Jie
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is an increasing public health concern with the aging of the global population. Understanding the genetic correlation and potential causal relationships between blood metabolites and AD may provide important insights into the metabolic dysregulation underlying this neurodegenerative disorder. Objective: The aim of this study was to investigate the causal relationship between blood metabolites and AD using Mendelian randomization (MR) analysis. Methods: Association data were obtained from three large-scale genome-wide association studies of 486 blood metabolites (N = 7,824), AD (71,880 cases and 383,378 controls), early-onset AD (N = 303,760), and late-onset …AD (N = 307,112). Causal associations between blood metabolites and AD were assessed using inverse variance weighting (IVW), MR-Egger, and weighted median methods. Bidirectional two-sample MR analysis was used to identify causal blood metabolites. MR-PRESSO, MR-Egger, and Cochran-Q were used to quantify instrumental variable heterogeneity and horizontal pleiotropy. Results: Using MR and sensitivity analysis, we identified 40 blood metabolites with potential causal associations with AD. After applying false discovery rate (FDR) correction, two metabolites, gamma-glutamylphenylalanine (OR = 1.15, 95% CI: 1.06–1.24, p = 3.88×10–4 , q = 0.09) and X-11317 (OR = 1.16, 95% CI: 1.08–1.26, p = 1.14×10–4 , q = 0.05), retained significant associations with AD. Reverse MR analysis indicated no significant causal effect of AD on blood metabolites. No significant instrumental variable heterogeneity or horizontal pleiotropy was found. Conclusions: This two-sample MR study provides compelling evidence for a potential causal relationship between blood metabolic dysregulation and susceptibility to AD. Further investigation of the biological relevance of the identified metabolites to AD and additional supporting evidence is warranted. Show more
Keywords: Alzheimer’s disease, blood metabolites, causal inference, Mendelian randomization
DOI: 10.3233/JAD-230985
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Lazarova, Maria I. | Tsvetanova, Elina R. | Georgieva, Almira P. | Stefanova, Miroslava O. | Uzunova, Diamara N. | Denev, Petko N. | Tasheva, Krasimira N.
Article Type: Research Article
Abstract: Background: The cholinergic neuronal loss in the basal forebrain and increasing brain oxidative stress are one of the main features of the brain suffering from Alzheimer’s disease. Marrubium vulgare (M. vulgare ), commonly known as ‘white horehound,’ possesses a variety of valuable properties, such as antioxidative, anti-inflammatory, and antidiabetic activities. Moreover, it possesses neuromodulatory properties that could potentially impact short-term memory functions. Objective: The present study was undertaken to investigate the preventive effects of water M. vulgare extract on working memory, cholinergic neurotransmission, and oxidative stress in rats with scopolamine (Sco)-induced dementia. Methods: Male …Wistar rats (200–250 g) were divided into four experimental groups. The plant extract was administered orally for 21 days, and Sco (2 mg/kg) was administered intraperitoneally for 11 consecutive days. The behavioral performance of the animals was evaluated by the T-maze test. The effect of the extract on acetylcholinesterase (AChE) activity and antioxidant status in cortex and hippocampus were also monitored. Results: Our experimental data revealed that treatment with M. vulgare significantly increased the percentage of correct choices of rats with Sco-induced dementia in the T maze test (by 38%, p < 0.05). Additionally, it reduced AChE activity in the hippocampus (by 20%, p < 0.05) and alleviated oxidative stress induced by Sco, particularly in the cortex. Conclusions: M. vulgare water extract demonstrated working memory preserving effect in rats with Sco-induced dementia, AChE inhibitory activity and in vivo antioxidant potential, and deserve further attention. Show more
Keywords: Acetylcholinesterase, Alzheimer’s disease, Marrubium vulgare, oxidative stress, scopolamine-induced dementia, T-maze test
DOI: 10.3233/JAD-231011
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Cesana, Bruno Mario | Bergh, Sverre | Ciccone, Alfonso | Cognat, Emmanuel | Fabbo, Andrea | Fascendini, Sara | Frisoni, Giovanni B. | Froelich, Lutz | Handels, Ron | Jori, Maria Cristina | Mecocci, Patrizia | Merlo, Paola | Peters, Oliver | Tsolaki, Magda | Defanti, Carlo Alberto
Article Type: Research Article
Abstract: Background: Nursing home placement (NHP) can be the final step of patients with Alzheimer’s disease. Objective: We aimed to identify NHP predictors among 508 people with dementia with a 3-year follow-up. Methods: We analyzed data from the international observational RECage study, involving 508 people with especially Alzheimer’s disease and comparing a cohort enrolled by five centers with a Special Care Unit for BPSD (behavioral and psychological symptoms of dementia) and another one enrolled by six centers lacking this facility. The tertiary objective of the study was to assess the possible role of the SCU-B in delaying …NHP. We assessed the relationship of the baseline characteristics with NHP by means of univariate analysis followed by Cox’s multivariate model. Results: Patients’ mean age was 78.1 years, 54.9% were women. Diagnosis mean age was 75.4 (±8.32) years; the main diagnosis was Alzheimer’s disease (296; 58.4%). During follow-up, 96 (18.9%) patients died and 153 (30.1%) were institutionalized without a statistically significant difference between the two cohorts (p = 0.9626). The mean NHP time was 902 (95% CI: 870–934). The multivariable analysis without death as a competing risk retained four independent predictors of NHP: age increase (hazard ratio (HR) = 1.023, 95% CI: 1.000–1.046), patient education level increase (HR = 1.062, 95% CI: 1.024–1.101), Neuropsychiatric Inventory total increase (HR = 1.018; 95% CI: 1.011–1.026), and total Mini-Mental State Examination as a favorable factor (HR = 0.948, 95% CI: 0.925–0.971). Gender (females versus males: HR = 1.265, 95% CI: 0.899–1.781) was included in the final Cox’s model for adjusting the estimates for. Conclusions: Our data partially agree with the predictors of NHP in literature including the effect of high education level. No caregivers’ factors were statistically significant. Clinical trial registration: NCT03507504. Show more
Keywords: Alzheimer’s disease, dementia, nursing home placement, predictive factors
DOI: 10.3233/JAD-230878
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Sánchez-Soblechero, Antonio | López-García, Sara | Lage, Carmen | Fernández-Matarrubia, Marta | Irure, Juan | López-Hoyos, Marcos | Jiménez-Bonilla, Julio | Quirce, Remedios | de Arcocha-Torres, María | Cuenca-Vera, Oriana | Martín-Arroyo, Juan | Martínez-Dubarbie, Francisco | Pozueta, Ana | García-Martínez, María | Infante, Jon | Sánchez-Juan, Pascual | Rodríguez-Rodríguez, Eloy
Article Type: Research Article
Abstract: Background: The optimal cut-off for Alzheimer’s disease (AD) CSF biomarkers remains controversial. Objective: To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11 C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aβ1–42 , pTau, tTau, and Aβ1–42 /Aβ1–40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods: CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) …were performed in all the patients. We established a cut-off for each single biomarker and Aβ1–42 /Aβ1–40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results: One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aβ1–42 /Aβ1–40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions: We established our sample’s best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer’s. Show more
Keywords: Alzheimer’s disease, amyloid positron emission tomography (a-PET), ATN classification, cerebrospinal fluid biomarkers (tTau, pTau, Aβ1–42 and Aβ1–42/Aβ1–40), 11C-Pittsburgh compound B, cut-off, data-driven cut-off, PET-driven cut-off
DOI: 10.3233/JAD-230678
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Ceyzériat, Kelly | Jaques, Emma | Gloria, Yesica | Badina, Aurélien | Millet, Philippe | Koutsouvelis, Nikolaos | Dipasquale, Giovanna | Frisoni, Giovanni B. | Zilli, Thomas | Garibotto, Valentina | Tournier, Benjamin B.
Article Type: Research Article
Abstract: Background: Low-dose radiation therapy (LD-RT) has demonstrated in preclinical and clinical studies interesting properties in the perspective of targeting Alzheimer’s disease (AD), including anti-amyloid and anti-inflammatory effects. Nevertheless, studies were highly heterogenous with respect to total doses, fractionation protocols, sex, age at the time of treatment and delay post treatment. Recently, we demonstrated that LD-RT reduced amyloid peptides and inflammatory markers in 9-month-old TgF344-AD (TgAD) males. Objective: As multiple studies demonstrated a sex effect in AD, we wanted to validate that LD-RT benefits are also observed in TgAD females analyzed at the same age. Methods: Females …were bilaterally treated with 2 Gy×5 daily fractions, 2 Gy×5 weekly fractions, or 10 fractions of 1 Gy delivered twice a week. The effect of each treatment on amyloid load and inflammation was evaluated using immunohistology and biochemistry. Results: A daily treatment did not affect amyloid and reduced only microglial-mediated inflammation markers, the opposite of the results obtained in our previous male study. Moreover, altered fractionations (2 Gy×5 weekly fractions or 10 fractions of 1 Gy delivered twice a week) did not influence the amyloid load or neuroinflammatory response in females. Conclusions: A daily treatment consequently appears to be the most efficient for AD. This study also shows that the anti-amyloid and anti-inflammatory response to LD-RT are, at least partly, two distinct mechanisms. It also emphasizes the necessity to assess the sex impact when evaluating responses in ongoing pilot clinical trials testing LD-RT against AD. Show more
Keywords: Alzheimer’s disease, amyloid, low-dose radiation therapy, microglial response
DOI: 10.3233/JAD-231153
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Xie, Xin-Yan | Huang, Lin-Ya | Cheng, Gui-Rong | Liu, Dan | Hu, Fei-Fei | Zhang, Jing-Jing | Han, Gang-Bin | Liu, Xiao-Chang | Wang, Jun-Yi | Zhou, Juan | Zeng, De-Yang | Liu, Jing | Nie, Qian-Qian | Song, Dan | Yu, Ya-Fu | Hu, Chen-Lu | Fu, Yi-Di | Li, Shi-Yue | Cai, Cheng | Cui, Yu-Yang | Cai, Wan-Ying | Li, Yi-Qing | Fan, Ren-Jia | Wan, Hong | Xu, Lang | Ou, Yang-Ming | Chen, Xing-Xing | Zhou, Yan-Ling | Chen, Yu-Shan | Li, Jin-Quan | Wei, Zhen | Wu, Qiong | Mei, Yu-Fei | Tan, Wei | Song, Shao-Jun | Zeng, Yan
Article Type: Research Article
Abstract: Background: As a prodromal stage of dementia, significant emphasis has been placed on the identification of modifiable risks of mild cognitive impairment (MCI). Research has indicated a correlation between exposure to air pollution and cognitive function in older adults. However, few studies have examined such an association among the MCI population inChina. Objective: We aimed to explore the association between air pollution exposure and MCI risk from the Hubei Memory and Aging Cohort Study. Methods: We measured four pollutants from 2015 to 2018, 3 years before the cognitive assessment of the participants. Logistic regression models were …employed to calculate odds ratios (ORs) to assess the relationship between air pollutants and MCI risk. Results: Among 4,205 older participants, the adjusted ORs of MCI risk for the highest quartile of PM2.5 , PM10 , O3 , and SO2 were 1.90 (1.39, 2.62), 1.77 (1.28, 2.47), 0.56 (0.42, 0.75), and 1.18 (0.87, 1.61) respectively, compared with the lowest quartile. Stratified analyses indicated that such associations were found in both males and females, but were more significant in older participants. Conclusions: Our findings are consistent with the growing evidence suggesting that air pollution increases the risk of mild cognitive decline, which has considerable guiding significance for early intervention of dementia in the older population. Further studies in other populations and broader geographical areas are warranted to validate these findings. Show more
Keywords: Air pollution, Hubei Memory and Aging Cohort Study, mild cognitive impairment, older Chinese population
DOI: 10.3233/JAD-231186
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Trieu, Calvin | van Harten, Argonde C. | Leeuwis, Anna E. | Exalto, Lieza G. | Hooghiemstra, Astrid M. | Verberk, Inge M.W. | Allaart, Cor P. | Brunner-La Rocca, Hans-Peter | Kappelle, L. Jaap | van Oostenbrugge, Robert J. | Biessels, Geert-Jan | Teunissen, Charlotte E. | van der Flier, Wiesje M.
Article Type: Research Article
Abstract: Background: We hypothesize that Alzheimer’s disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40 ), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models …with terms for biomarker, time and biomarker* time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (–0.14±0.04) and memory (–0.31±0.09) and with steeper decline in global cognition (–0.07±0.02), memory (–0.09±0.04), attention (–0.05±0.02), and language (–0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (–0.22±0.05), memory (–0.43±0.10), attention (–0.14±0.06), language (–0.15±0.05), and executive functioning (–0.15±0.05) and steeper decline in global cognition (–0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (–0.16±0.04), memory (–0.28±0.09), attention (–0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases. Show more
Keywords: Alzheimer’s disease, carotid stenosis, cognitive dysfunction, heart failure, vascular dementia
DOI: 10.3233/JAD-231096
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Brooks, Wesley Harrell
Article Type: Research Article
Abstract: A hypothesis of Alzheimer’s disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer’s disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome …21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka “nucleolar satellite”) with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer’s, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases. Show more
Keywords: Alu, Alzheimer’s disease, amyloid-β, autoimmune disease tautology, epigenetics, inactive X chromosome, nucleolus, polyamines, tau
DOI: 10.3233/JAD-231184
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2024
Authors: Polis, Baruh | Samson, Abraham O.
Article Type: Review Article
Abstract: Animal models, particularly transgenic mice, are extensively used in Alzheimer’s disease (AD) research to emulate key disease hallmarks, such as amyloid plaques and neurofibrillary tangles formation. Although these models have contributed to our understanding of AD pathogenesis and can be helpful in testing potential therapeutic interventions, their reliability is dubious. While preclinical studies have shown promise, clinical trials often yield disappointing results, highlighting a notable gap and disparity between animal models and human AD pathology. Existing models frequently overlook early-stage human pathologies and other key AD characteristics, thereby limiting their application in identifying optimal therapeutic interventions. Enhancing model reliability necessitates …rigorous study design, comprehensive behavioral evaluations, and biomarker utilization. Overall, a nuanced understanding of each model’s neuropathology, its fidelity to human AD, and its limitations is essential for accurate interpretation and successful translation of findings. This article analyzes the discrepancies between animal models and human AD pathology that complicate the translation of findings from preclinical studies to clinical applications. We also delve into AD pathogenesis and attributes to propose a new perspective on this pathology and deliberate over the primary limitations of key experimental models. Additionally, we discuss several fundamental problems that may explain the translational failures and suggest some possible directions for more effective preclinical studies. Show more
Keywords: Aging, Alzheimer’s disease, animal models, validity
DOI: 10.3233/JAD-240058
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Cogut, Valeria | McNeely, Taylor L. | Bussian, Tyler J. | Graves, Sara I. | Baker, Darren J.
Article Type: Research Article
Abstract: Background: Caloric restriction (CR) has been recognized for its benefits in delaying age-related diseases and extending lifespan. While its effects on amyloid pathology in Alzheimer’s disease (AD) mouse models are well-documented, its effects on tauopathy, another hallmark of AD, are less explored. Objective: To assess the impact of a short-term 30% CR regimen on age-dependent spatial learning deficits and pathological features in a tauopathy mouse model. Methods: We subjected male PS19 tau P301S (hereafter PS19) and age-matched wildtype mice from two age cohorts (4.5 and 7.5 months old) to a 6-week 30% CR …regimen. Spatial learning performance was assessed using the Barnes Maze test. Tau pathology, neuroinflammation, hippocampal cell proliferation, and neurogenesis were evaluated in the older cohort by immunohistochemical staining and RT-qPCR. Results: CR mitigated age-dependent spatial learning deficits in PS19 mice but exhibited limited effects on tau pathology and the associated neuroinflammation. Additionally, we found a decrease in hippocampal cell proliferation, predominantly of Iba1+ cells. Conclusions: Our findings reinforce the cognitive benefits conferred by CR despite its limited modulation of disease pathology. Given the pivotal role of microglia in tau-driven pathology, the observed reduction in Iba1+ cells under CR suggests potential therapeutic implications, particularly if CR would be introduced early in disease progression. Show more
Keywords: Alzheimer’s disease, calorie restriction, microglia, spatial learning, tauopathy
DOI: 10.3233/JAD-231117
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Mattke, Soeren | Jun, Hankyung | Chu, Samantha | Hanson, Mark
Article Type: Research Article
Abstract: Background: Individuals dually eligible for Medicare and Medicaid (duals) may face greater obstacles to access to disease-modifying Alzheimer’s treatments in spite of their higher disease burden, because of clinicians’ reluctance to accept Medicaid and the so-called “lesser of” policy, under which Medicaid may pay providers lower rates. Objective: To project differential wait times for duals compared to Medicare-only beneficiaries by state. Methods: We used State Medicaid payment policy and Medicare enrollment data and a Markov model to predict differential wait times for duals and non-duals from 2023 to 2050. We estimated available diagnostic appointments by state …for both groups based on reluctance of clinicians to accept Medicaid and the “lesser of” policy for each year. Results: We estimate overall average wait times of almost two years (22.9 months) but almost three times as long for duals (59.8 months) than non-duals (20.7 months) because of higher disease burden. The effects of Medicaid payment policy would increase average wait times for duals to 89 months with 20 states having wait times of 99 months or more, which would effectively deprive duals of access. Conclusions: The added average wait times in many states would effectively deprive duals from access to treatment and translate into avoidable disease progression and mortality. Policy interventions to reduce financial and nonfinancial obstacles are dearly needed to avoid deepening disparities. Examples are coverage arrangements that integrate Medicare and Medicaid coverage, covering the co-payment for physician services in full, and stricter network adequacy requirements for Medicaid Managed Care plans. Show more
Keywords: Access to care, Alzheimer’s disease, diagnosis, disease-modifying treatment, disparities, dual eligibility, medicare, medicaid, payment policy, wait times
DOI: 10.3233/JAD-231134
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Tseng, Wen-Yih Isaac | Hsu, Yung-Chin | Huang, Li-Kai | Hong, Chien-Tai | Lu, Yueh-Hsun | Chen, Jia-Hung | Fu, Chin-Kun | Chan, Lung
Article Type: Research Article
Abstract: Background: The effect of cholinesterase inhibitor (ChEI) on mild cognitive impairment (MCI) is controversial. Brain age has been shown to predict Alzheimer’s disease conversion from MCI. Objective: The study aimed to show that brain age is related to cognitive outcomes of ChEI treatment in MCI. Methods: Brain MRI, the Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) scores were retrospectively retrieved from a ChEI treatment database. Patients who presented baseline CDR of 0.5 and received ChEI treatment for at least 2 years were selected. Patients with stationary or improved cognition as verified …by the CDR and MMSE were categorized to the ChEI-responsive group, and those with worsened cognition were assigned to the ChEI-unresponsive group. A gray matter brain age model was built with a machine learning algorithm by training T1-weighted MRI data of 362 healthy participants. The model was applied to each patient to compute predicted age difference (PAD), i.e. the difference between brain age and chronological age. The PADs were compared between the two groups. Results: 58 patients were found to fit the ChEI-responsive criteria in the patient data, and 58 matched patients that fit the ChEI-unresponsive criteria were compared. ChEI-unresponsive patients showed significantly larger PAD than ChEI-responsive patients (8.44±8.78 years versus 3.87±9.02 years, p = 0.0067). Conclusions: Gray matter brain age is associated with cognitive outcomes after 2 years of ChEI treatment in patients with the CDR of 0.5. It might facilitate the clinical trials of novel therapeutics for MCI. Show more
Keywords: Alzheimer’s disease, brain age, cholinesterase inhibitor, clinical dementia rating, cognitive outcome, magnetic resonance imaging, mild cognitive impairment, mini-mental state examination
DOI: 10.3233/JAD-231109
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Calderón-Garcidueñas, Lilian | Ayala, Alberto | Mukherjee, Partha S.
Article Type: Short Communication
Abstract: Air pollution exposures ought to be of significant interest for the United States (US) public as health issues will play a role in the 2024 elections. Citizens are not aware of the harmful brain impact of exposures to ubiquitous anthropogenic combustion emissions and friction-derived nanoparticles, industrial nanoplastics, the growing risk of wildfires, and the smoke plumes of soot. Ample consideration of pediatric and early adulthood hallmarks of Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis and associations with neuropsychiatric and neurodevelopmental disorders in the process of setting, reviewing, and implementing standards for particulate matter (PM)2.5 , ultrafine …PM, and industrial nanoparticles must be of interest to US citizens. Show more
Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, anthropogenic emissions control, frontotemporal lobar degeneration, nanoparticles, Parkinson’s disease, particulate air pollution, pediatric neurodegeneration, 2024 US elections, wildfires
DOI: 10.3233/JAD-231373
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2024
Authors: Zhang, Mengxue | Qu, Yanjie | Li, Qian | Gu, Chao | Zhang, Limin | Chen, Hongxu | Ding, Minrui | Zhang, Tong | Zhen, Rongrong | An, Hongmei
Article Type: Research Article
Abstract: Background: The development of Alzheimer’s disease (AD) can be divided into subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia. Early recognition of pre-AD stages may slow the progression of dementia. Objective: This study aimed to explore functional connectivity (FC) changes of the brain prefrontal cortex (PFC) in AD continuum using functional near-infrared spectroscopy (fNIRS), and to analyze its correlation with cognitive function. Methods: All participants underwent 48-channel fNIRS at resting-state. Based on Brodmann partitioning, the PFC was divided into eight subregions. The NIRSIT Analysis Tool (v3.7.5) was used to analyze mean ΔHbO2 and FC. …Spearman correlation analysis was used to examine associations between FC and cognitive function. Results: Compared with HC group, the mean ΔHbO2 and FC were different between multiple subregions in the AD continuum. Both mean ΔHbO2 in the left dorsolateral PFC and average FC decreased sequentially from SCD to MCI to AD groups. Additionally, seven pairs of subregions differed in FC among the three groups: the differences between the MCI and SCD groups were in heterotopic connectivity; the differences between the AD and SCD groups were in left intrahemispheric and homotopic connectivity; whereas the MCI and AD groups differed only in homotopic connectivity. Spearman correlation results showed that FCs were positively correlated with cognitive function. Conclusions: These results suggest that the left dorsolateral PFC may be the key cortical impairment in AD. Furthermore, there are different resting-state prefrontal network patterns in AD continuum, and the degree of cognitive impairment is positively correlated with reduced FC strength. Show more
Keywords: Alzheimer’s disease, cognitive decline, functional connectivity, functional near-infrared spectroscopy, prefrontal cortex, resting-state
DOI: 10.3233/JAD-230648
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Li, Yaqi | Xu, Xinming | Wang, Peilu | Chen, Xiqun | Yang, Qishan | Sun, Liang | Gao, Xiang
Article Type: Research Article
Abstract: Background: The literature presents conflicting results regarding the potential protective effect of prevalent cancer on the development of dementia and Alzheimer’s disease (AD). Objective: Association between cancer and subsequent risk of dementia and/or AD was reported previously, but survival bias has been of concern. Here, we aimed to calculate the lifetime risk of dementia and AD and evaluate the association of cancer history with these two conditions. Methods: In this retrospective analysis, we included 292,654 participants aged 60+ y during the follow-up and free of dementia at baseline, within the UK Biobank cohort. Lifetime risks of dementia …and AD were estimated in individuals with and without cancer history, and different durations of cancer exposure and cancer types. Results: During a median of 12.5 follow-up years, 5,044 new dementia and 2,141 AD cases were reported. Lifetime risks of dementia and AD were lower in cancer survivors compared to those without cancer, and this effect was more pronounced in participants with cancer history exposure≥5 years. Similar relationship was observed in individual cancer types, except for breast cancer. Conclusions: Results suggested an inverse association between cancer history and lifetime risk of dementia and AD, which may be modified by different cancer types and cancer exposure time. Show more
Keywords: Alzheimer’s disease, cancer, dementia, lifetime risk
DOI: 10.3233/JAD-231223
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Ruan, Yiming | Zheng, Darui | Guo, Wenxuan | Cao, Xuan | Qi, Wenzhang | Yuan, Qianqian | Zhang, Xulian | Liang, Xuhong | Zhang, Da | Xue, Chen | Xiao, Chaoyong
Article Type: Research Article
Abstract: Background: Mild cognitive impairment (MCI), the prodromal stage of Alzheimer’s disease, has two distinct subtypes: stable MCI (sMCI) and progressive MCI (pMCI). Early identification of the two subtypes has important clinical significance. Objective: We aimed to compare the cortico-striatal functional connectivity (FC) differences between the two subtypes of MCI and enhance the accuracy of differential diagnosis between sMCI and pMCI. Methods: We collected resting-state fMRI data from 31 pMCI patients, 41 sMCI patients, and 81 healthy controls. We chose six pairs of seed regions, including the ventral striatum inferior, ventral striatum superior, dorsal-caudal putamen, dorsal-rostral putamen, …dorsal caudate, and ventral-rostral putamen and analyzed the differences in cortico-striatal FC among the three groups, additionally, the relationship between the altered FC within the MCI subtypes and cognitive function was examined. Results: Compared to sMCI, the pMCI patients exhibited decreased FC between the left dorsal-rostral putamen and right middle temporal gyrus, the right dorsal caudate and right inferior temporal gyrus, and the left dorsal-rostral putamen and left superior frontal gyrus. Additionally, the altered FC between the right inferior temporal gyrus and right putamen was significantly associated with episodic memory and executive function. Conclusions: Our study revealed common and distinct cortico-striatal FC changes in sMCIs and pMCI across different seeds; these changes were associated with cognitive function. These findings can help us understand the underlying pathophysiological mechanisms of MCI and distinguish pMCI and sMCI in the early stage potentially. Show more
Keywords: Alzheimer’s disease, classification, functional connectivity, mild cognitive impairment, resting-state functional magnetic resonance imaging, striatum
DOI: 10.3233/JAD-231174
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Cummings, Jeffrey
Article Type: Article Commentary
Abstract: Better means of conducting more efficient clinical trials for the development of Alzheimer’s disease (AD) therapeutics are required. Adaptive clinical trial designs have many advantages based on the ability to make prespecified changes in the trial conduct depending on the ongoing experience in the trial. In their report in the Journal of Alzheimer’s Disease , Lee and colleagues show that in the past 25 years only 2.5% of AD clinical trials have used adaptive designs. The report calls attention to the opportunity to use adaptive designs more often in Phase 2 clinical trials to improve trial efficiency and accelerate treatment …development. Show more
Keywords: Adaptive design, ADCOMS, Alzheimer’s disease, clinical trial, lecanemab, parallel group
DOI: 10.3233/JAD-240145
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2024
Authors: Shui, Lan | Shibata, Dean | Chan, Kwun Chuen Gary | Zhang, Wenbo | Sung, Junhyoun | Haynor, David R.
Article Type: Research Article
Abstract: Background: Longitudinal magnetic resonance imaging (MRI) has been proposed for tracking the progression of Alzheimer’s disease (AD) through the assessment of brain atrophy. Objective: Detection of brain atrophy patterns in patients with AD as the longitudinal disease tracker. Methods: We used a refined version of orthonormal projective non-negative matrix factorization (OPNMF) to identify six distinct spatial components of voxel-wise volume loss in the brains of 83 subjects with AD from the ADNI3 cohort relative to healthy young controls from the ABIDE study. We extracted non-negative coefficients representing subject-specific quantitative measures of regional atrophy. Coefficients of brain …atrophy were compared to subjects with mild cognitive impairment and controls, to investigate the cross-sectional and longitudinal associations between AD biomarkers and regional atrophy severity in different groups. We further validated our results in an independent dataset from ADNI2. Results: The six non-overlapping atrophy components represent symmetric gray matter volume loss primarily in frontal, temporal, parietal and cerebellar regions. Atrophy in these regions was highly correlated with cognition both cross-sectionally and longitudinally, with medial temporal atrophy showing the strongest correlations. Subjects with elevated CSF levels of TAU and PTAU and lower baseline CSF Aβ42 values, demonstrated a tendency toward a more rapid increase of atrophy. Conclusions: The present study has applied a transferable method to characterize the imaging changes associated with AD through six spatially distinct atrophy components and correlated these atrophy patterns with cognitive changes and CSF biomarkers cross-sectionally and longitudinally, which may help us better understand the underlying pathology of AD. Show more
Keywords: Alzheimer’s disease, biomarkers, brain atrophy, longitudinal studies, magnetic resonance imaging
DOI: 10.3233/JAD-231149
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Love, Robert W.B.
Article Type: Research Article
Abstract: Alzheimer’s disease is the leading cause of dementia in the world. It affects 6 million people in the United States and 50 million people worldwide. Alzheimer’s disease is characterized by the accumulation of amyloid-β plaques (Aβ), an increase in tau protein neurofibrillary tangles, and a loss of synapses. Since the 1990s, removing and reducing Aβ has been the focus of Alzheimer’s treatment and prevention research. The accumulation of Aβ can lead to oxidative stress, inflammation, neurotoxicity, and eventually apoptosis. These insults impair signaling systems in the brain, potentially leading to memory loss and cognitive decline. Aniracetam is a safe, effective, …cognitive-enhancing drug that improves memory in both human and animal studies. Aniracetam may prevent the production and accumulation of Aβ by increasing α -secretase activity through two distinct pathways: 1) increasing brain derived neurotrophic factor expression and 2) positively modulating metabotropic glutamate receptors. This is the first paper to propose an evidence-based model for aniracetam reducing the accumulation and production of Aβ. Show more
Keywords: Aging, α-secretase, Alzheimer’s disease, amyloid plaques, aniracetam, BDNF, cognition, dementia, neurobiology, pharmacology
DOI: 10.3233/JAD-231247
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2024
Authors: Vijayan, Murali | Reddy, P. Hemachandra
Article Type: Research Article
Abstract: Background: The intricate and complex molecular mechanisms that underlie the progression of Alzheimer’s disease (AD) have prompted a concerted and vigorous research endeavor aimed at uncovering potential avenues for therapeutic intervention. Objective: This study aims to elucidate the role of miRNA PC-5P-12969 in the pathogenesis of AD. Methods: We assessed the differential expression of miRNA PC-5P-12969 in postmortem AD brains, AD animal and cell models using real-time reverse-transcriptase RT-PCR, we also checked the gene and protein expression of GSK3α and APP. Results: Our investigation revealed a notable upregulation of miRNA PC-5P-12969 in postmortem …brains of AD patients, in transgenic mouse models of AD, and in mutant APP overexpressing-HT22 cells. Additionally, our findings indicate that overexpression of miRNA PC-5P-12969 exerts a protective effect on cell survival, while concurrently mitigating apoptotic cell death. Further-more, we established a robust and specific interaction between miRNA PC-5P-12969 and GSK3α . Our luciferase reporter assays provided confirmation of the binding between miRNA PC-5P-12969 and the 3′-UTR of the GSK3α gene. Manipulation of miRNA PC-5P-12969 levels in cellular models of AD yielded noteworthy alterations in the gene and protein expression levels of both GSK3α and APP. Remarkably, the manipulation of miRNA PC-5P-12969 levels yielded significant enhancements in mitochondrial respiration and ATP production, concurrently with a reduction in mitochondrial fragmentation, thus unveiling a potential regulatory role of miRNA PC-5P-12969 in these vital cellular processes. Conclusions: In summary, this study sheds light on the crucial role of miRNA PC-5P-12969 and its direct interaction with GSK3α in the context of AD. Show more
Keywords: Alzheimer’s disease, amyloid-β , AβPP, GSK3α , microRNA, mitochondrial fragmentation, mitochondrial respiration, postmortem brains, therapeutics
DOI: 10.3233/JAD-231281
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Gelfo, Francesca | Petrosini, Laura | Mandolesi, Laura | Landolfo, Eugenia | Caruso, Giulia | Balsamo, Francesca | Bonarota, Sabrina | Bozzali, Marco | Caltagirone, Carlo | Serra, Laura
Article Type: Review Article
Abstract: Evidence in the literature indicates that aerobic physical activity may have a protective role in aging pathologies. However, it has not been clarified whether different types of aerobic exercise produce different effects. In particular, these potential differences have not been explored in patients with Alzheimer’s disease (AD). The present narrative review has the specific aim of evaluating whether land (walking/running) and water (swimming) aerobic activities exert different effects on cognitive functions and neural correlates in AD patients. In particular, the investigation is carried out by comparing the evidence provided from studies on AD animal models and on patients. On the …whole, we ascertained that both human and animal studies documented beneficial effects of land and water aerobic exercise on cognition in AD. Also, the modulation of numerous biological processes is documented in association with structural modifications. Remarkably, we found that aerobic activity appears to improve cognition per se , independently from the specific kind of exercise performed. Aerobic exercise promotes brain functioning through the secretion of molecular factors from skeletal muscles and liver. These molecular factors stimulate neuroplasticity, reduce neuroinflammation, and inhibit neurodegenerative processes leading to amyloid-β accumulation. Additionally, aerobic exercise improves mitochondrial activity, reducing oxidative stress and enhancing ATP production. Aerobic activities protect against AD, but implementing exercise protocols for patients is challenging. We suggest that health policies and specialized institutions should direct increasing attention on aerobic activity as lifestyle modifiable factor for successful aging and age-related conditions. Show more
Keywords: Aerobic activity, Alzheimer’s disease, animal models, brain/cognitive/neural reserve, cognition, humans, neural plasticity, physical exercise
DOI: 10.3233/JAD-231279
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Robinson, Andrew C. | Bin Rizwan, Tawfique | Davidson, Yvonne S. | Minshull, James | Tinkler, Phillip | Payton, Antony | Mann, David M.A. | Roncaroli, Federico
Article Type: Research Article
Abstract: Background: While mid-life hypertension represents a risk factor for the development of Alzheimer’s disease (AD), the risk after the age of 65 is less certain. Establishing relationships between late life hypertension and the pathological changes of AD could be crucial in understanding the relevance of blood pressure as a risk factor for this disorder. Objective: We investigated associations between self-reported late-life hypertension, cognitive status and AD pathology at death. The impact of antihypertensive medication was also examined. Methods: Using the Cornell Medical Index questionnaire, we ascertained whether participants had ever reported hypertension. We also noted use …of antihypertensive medication. The donated brains of 108 individuals were assessed for AD pathology using consensus guidelines. Statistical analysis aimed to elucidate relationships between hypertension and AD pathology. Results: We found no associations between self-reported hypertension and cognitive impairment at death. However, those with hypertension were significantly more likely to exhibit lower levels of AD pathology as measured by Thal phase, Braak stage, CERAD score, and NIA-AA criteria—even after controlling for sex, level of education and presence of APOE ɛ 4 allele(s). No significant associations could be found when examining use of antihypertensive medications. Conclusions: Our findings suggest that late-life hypertension is associated with less severe AD pathology. We postulate that AD pathology may be promoted by reduced cerebral blood flow. Show more
Keywords: Alzheimer’s disease, dementia, hypertension, neuropathology
DOI: 10.3233/JAD-231429
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
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