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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: Puentes-Díaz, Nicolás | Chaparro, Diego | Reyes-Marquez, Viviana | Morales-Morales, David | Flores-Gaspar, Areli | Alí-Torres, Jorge
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia representing from 60% to 70% of the cases globally. It is a multifactorial disease that, among its many pathological characteristics, has been found to provoke the metal ion dysregulation in the brain, along with an increase in the oxidative stress. There is proof that metallic complexes formed by the amyloid-β peptide (Aβ) and extraneuronal copper can catalyze the production of reactive oxygen species, leading to an increase in oxidative stress, promoting neuronal death. Due to this interaction, bioavailable copper has become an important redox active target to consider within …the search protocols of multifunctional agents for AD’s treatment. Objective: In this study, we examined by using bioinformatics and electronic structure calculations the potential application of 44 salen-type copper chelating ligands and 12 further proposed molecules as possible multifunctional agents in the context of AD. Methods: The candidates were evaluated by combining bioinformatic tools and electronic structure calculations, which allowed us to classify the molecules as potential antioxidants, redistributor-like compounds, and the newly proposed suppressor mechanism. Results: This evaluation demonstrate that salen-type ligands exhibit properties suitable for interfering in the chain of copper-induced oxidative stress reactions present in AD and potential redistributor and suppressor activity for copper ions. Finally, a novel set of plausible candidates is proposed and evaluated. Conclusion: According to the evaluated criteria, a subset of 13 salen-type candidates was found to exhibit promissory pharmacological properties in the AD framework and were classified according to three plausible action mechanisms. Show more
Keywords: Alzheimer’s disease, copper binding affinities, density functional theory calculations, salen-type ligands, standard reduction potentials
DOI: 10.3233/JAD-230542
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Chum, Phoebe P. | Bishara, Mary A. | Solis, Summer R. | Behringer, Erik J.
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is associated with impaired cerebral circulation which underscores diminished delivery of blood oxygen and nutrients to and throughout the brain. In the 3xTg-AD mouse model, we have recently found that > 10 cerebrovascular miRNAs pertaining to vascular permeability, angiogenesis, and inflammation (e.g., let-7d, miR-99a, miR-132, miR-133a, miR-151-5p, and miR-181a) track early development of AD. Further, endothelial-specific miRNAs (miR-126-3p, miR-23a/b, miR-27a) alter with onset of overall AD pathology relative to stability of smooth muscle/pericyte-specific miRNAs (miR-143, miR-145). Objective: We tested the hypothesis that cerebrovascular miRNAs indicating AD pathology share mRNA targets that regulate key endothelial cell functions …such as angiogenesis, vascular permeability, and blood flow regulation. Methods: As detected by NanoString nCounter miRNA Expression panel for 3xTg-AD mice, 61 cerebrovascular miRNAs and respective mRNA targets were examined using Ingenuity Pathway Analysis for canonical Cardiovascular (Cardio) and Nervous System (Neuro) Signaling. Results: The number of targets regulated per miRNA were 21±2 and 33±3 for the Cardio and Neuro pathways respectively, whereby 14±2 targets overlap among pathways. Endothelial miRNAs primarily target members of the PDE, PDGF, SMAD, and VEGF families. Individual candidates regulated by≥4 miRNAs that best mark AD pathology presence in 3xTg-AD mice include CFL2, GRIN2B, PDGFB, SLC6A1, SMAD3, SYT3, and TNFRSF11B. Conclusion: miRNAs selective for regulation of endothelial function and respective downstream mRNA targets support a molecular basis for dysregulated cerebral blood flow regulation coupled with enhanced cell growth, proliferation, and inflammation. Show more
Keywords: Alzheimer’s disease, brain endothelium, mRNA targets, vascular dysfunction
DOI: 10.3233/JAD-230300
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-48, 2023
Authors: Liang, Jingjing | LaFleur, Bonnie | Hussainy, Sadiya | Perry, George
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly marked by central nervous system (CNS) neuronal loss and amyloid plaques. FAM222A , encoding an amyloid plaque core protein, is an AD brain atrophy susceptibility gene that mediates amyloid-β aggregation. However, the expression interplay between FAM222A and other AD-related pathway genes is unclear. Objective: Our goal was to study FAM222A ’s whole-genome co-expression profile in multiple tissues and investigate its interplay with other AD-related genes. Methods: We analyzed gene expression correlations in Genotype-Tissue Expression (GTEx) tissues to identify FAM222A co-expressed …genes and performed functional enrichment analysis on identified genes in CNS system. Results: Genome-wide gene expression profiling identified 673 genes significantly correlated with FAM222A (p < 2.5×10–6 ) in 48 human tissues, including 298 from 13 CNS tissues. Functional enrichment analysis revealed that FAM222A co-expressed CNS genes were enriched in multiple AD-related pathways. Gene co-expression network analysis for identified genes in each brain region predicted other disease associated genes with similar biological function. Furthermore, co-expression of 25 out of 31 AD-related pathways genes with FAM222A was replicated in brain samples from 107 aged subjects from the Aging, Dementia and TBI Study. Conclusion: This gene co-expression study identified multiple AD-related genes that are associated with FAM222A , indicating that FAM222A and AD-associated genes can be active simultaneously in similar biological processes, providing evidence that supports the association of FAM222A with AD. Show more
Keywords: Alzheimer’s disease, FAM222A, gene co-expression network analysis, neurodegeneration, transcriptomics
DOI: 10.3233/JAD-221241
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: Lardelli, Michael | Baer, Lachlan | Hin, Nhi | Allen, Angel | Pederson, Stephen Martin | Barthelson, Karissa
Article Type: Research Article
Abstract: The degree to which non-human animals can be used to model Alzheimer’s disease is a contentious issue, particularly as there is still widespread disagreement regarding the pathogenesis of this neurodegenerative dementia. The currently popular transgenic models are based on artificial expression of genes mutated in early onset forms of familial Alzheimer’s disease (EOfAD). Uncertainty regarding the veracity of these models led us to focus on heterozygous, single mutations of endogenous genes (knock-in models) as these most closely resemble the genetic state of humans with EOfAD, and so incorporate the fewest assumptions regarding pathological mechanism. We have generated a number of …lines of zebrafish bearing EOfAD-like and non-EOfAD-like mutations in genes equivalent to human PSEN1 , PSEN2 , and SORL1 . To analyze the young adult brain transcriptomes of these mutants, we exploited the ability of zebrafish to produce very large families of simultaneous siblings composed of a variety of genotypes and raised in a uniform environment. This “intra-family” analysis strategy greatly reduced genetic and environmental “noise” thereby allowing detection of subtle changes in gene sets after bulk RNA sequencing of entire brains. Changes to oxidative phosphorylation were predicted for all EOfAD-like mutations in the three genes studied. Here we describe some of the analytical lessons learned in our program combining zebrafish genome editing with transcriptomics to understand the molecular pathologies of neurodegenerative disease. Show more
Keywords: Alzheimer’s disease, early onset Alzheimer’s disease, gene expression profiling, genetic, models, transcriptome, zebrafish
DOI: 10.3233/JAD-230522
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023
Authors: Yan, Ran | Wang, Wenjing | Yang, Wen | Huang, Masha | Xu, Wei
Article Type: Research Article
Abstract: Background: Late-onset Alzheimer’s disease (LOAD) is the most common type of dementia, but its pathogenesis remains unclear, and there is a lack of simple and convenient early diagnostic markers to predict the occurrence. Objective: Our study aimed to identify diagnostic candidate genes to predict LOAD by machine learning methods. Methods: Three publicly available datasets from the Gene Expression Omnibus (GEO) database containing peripheral blood gene expression data for LOAD, mild cognitive impairment (MCI), and controls (CN) were downloaded. Differential expression analysis, the least absolute shrinkage and selection operator (LASSO), and support vector machine recursive feature elimination …(SVM-RFE) were used to identify LOAD diagnostic candidate genes. These candidate genes were then validated in the dataset validation group and clinical samples, and a LOAD prediction model was established. Results: LASSO and SVM-RFE analyses identified 3 mitochondria-related genes (MRGs) as candidate genes, including NDUFA1, NDUFS5, and NDUFB3. In the verification of 3 MRGs, the AUC values showed that NDUFA1 , NDUFS5 had better predictability. We also verified the candidate MRGs in MCI groups, the AUC values showed a good performance. We then used NDUFA1, NDUFS5 and age to build a LOAD diagnostic model and AUC was 0.723. Results of qRT-PCR experiments showed that the three candidate genes were expressed significantly lower in the LOAD and MCI groups when compared to CN. Conclusion: Two mitochondrial-related candidate genes, NDUFA1 and NDUFS5, were identified as diagnostic markers for LOAD and MCI. Combining these two candidate genes with age, a LOAD diagnostic prediction model was successfully constructed. Show more
Keywords: Alzheimer’s disease, biomarker, late-onset Alzheimer’s disease, immune cells, machine learning, mild cognitive impairment, mitochondria related genes
DOI: 10.3233/JAD-230314
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2023
Authors: Huang, Yiyao | Driedonks, Tom A.P. | Cheng, Lesley | Turchinovich, Andrey | Pletniková, Olga | Redding-Ochoa, Javier | Troncoso, Juan C. | Hill, Andrew F. | Mahairaki, Vasiliki | Zheng, Lei | Witwer, Kenneth W.
Article Type: Research Article
Abstract: Background: Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer’s disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. Brain tissue-derived EVs (bdEVs) are particularly relevant, as they may offer valuable insights about the tissue of origin. However, there is limited research on diverse ncRNA species in bdEVs in AD. Objective: This study explored whether the non-coding RNA composition of EVs isolated from post-mortem brain tissue is related to AD pathogenesis. Methods: bdEVs from age-matched late-stage AD patients (n = 23) and controls (n = 10) …that had been separated and characterized in our previous study were used for RNA extraction, small RNA sequencing, and qPCR verification. Results: Significant differences of non-coding RNAs between AD and controls were found, especially for miRNAs and tRNAs. AD pathology-related miRNA and tRNA differences of bdEVs partially matched expression differences in source brain tissues. AD pathology had a more prominent association than biological sex with bdEV miRNA and tRNA components in late-stage AD brains. Conclusions: Our study provides further evidence that EV non-coding RNAs from human brain tissue, including but not limited to miRNAs, may be altered and contribute to AD pathogenesis. Show more
Keywords: Alzheimer’s disease, brain, ectosomes, exosomes, extracellular vesicles, microvesicles, miRNAs, non-coding RNAs, RNA sequencing, tRNAs
DOI: 10.3233/JAD-230872
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023
Authors: Sultana, Munira | Camicioli, Richard | Dixon, Roger A. | Whitehead, Shawn | Pieruccini-Faria, Frederico | Petrotchenko, Evgeniy | Speechley, Mark | Borchers, Christoph H. | Montero-Odasso, Manuel
Article Type: Research Article
Abstract: Background: Older adults presenting with dual-decline in cognition and walking speed face a 6-fold higher risk for dementia compared with those showing no decline. We hypothesized that the metabolomics profile of dual-decliners would be unique even before they show signs of decline in cognition and gait speed. Objective: The objective of this study was to determine if plasma metabolomics signatures can discriminate dual-decliners from no decliners, purely cognitive decliners, and purely motor decliners prior to decline. Methods: A retrospective cross-sectional study using baseline plasma for untargeted metabolomics analyses to investigate early signals of later dual-decline status …in study participants (n = 76) with convenient sampling. Dual-decline was operationalized as decline in gait speed (>10 cm/s) and cognition (>2 points decline in Montreal Cognitive Assessment score) on at least two consecutive 6-monthly assessments. The participants’ decliner status was evaluated 3 years after the blood sample was collected. Pair-wise comparison of detected compounds was completed using principal components and hierarchical clustering analyses. Results: Analyses did not detect any cluster separation in untargeted metabolomes across baseline groups. However, follow-up analyses of specific molecules detected 4 compounds (17-Hydroxy-12-(hydroxymethyl)-10-oxo-8 oxapentacyclomethyl hexopyranoside, Fleroxacin, Oleic acid, and 5xi-11,12-Dihydroxyabieta-8(14),9(11),12-trien-20-oic acid) were at significantly higher concentration among the dual-decliners compared to non-decliners. The pure cognitive decliner group had significantly lower concentration of six compounds (1,3-nonanediol acetate, 4-(2-carboxyethyl)-2-methoxyphenyl beta-D-glucopyranosiduronic acid, oleic acid, 2E-3-[4-(sulfo-oxy)phenyl] acrylic acid, palmitelaidic acid, and myristoleic acid) compared to the non-decliner group. Conclusions: The unique metabolomics profile of dual-decliners warrants follow-up metabolomics analysis. Results may point to modifiable pathways. Show more
Keywords: Aging, Alzheimer’s disease, cognition, diagnosis, gait, metabolomics
DOI: 10.3233/JAD-230683
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023
Authors: Nelson, Doug | Thompson, Kevin J. | Wang, Lushan | Wang, Zengtao | Eberts, Paulina | Azarin, Samira M. | Kalari, Krishna R. | Kandimalla, Karunya K.
Article Type: Research Article
Abstract: Background: A strong body of evidence suggests that cerebrovascular pathologies augment the onset and progression of Alzheimer’s disease (AD). One distinctive aspect of this cerebrovascular dysfunction is the degeneration of brain pericytes—often overlooked supporting cells of blood-brain barrier endothelium. Objective: The current study investigates the influence of pericytes on gene and protein expressions in the blood-brain barrier endothelium, which is expected to facilitate the identification of pathophysiological pathways that are triggered by pericyte loss and lead to blood-brain barrier dysfunction in AD. Methods: Bioinformatics analysis was conducted on the RNA-Seq expression counts matrix (GSE144474), which compared …solo-cultured human blood-brain barrier endothelial cells against endothelial cells co-cultured with human brain pericytes in a non-contact model. We constructed a similar cell culture model to verify protein expression using western blots. Results: The insulin resistance and ferroptosis pathways were found to be enriched. Western blots of the insulin receptor and heme oxygenase expressions were consistent with those observed in RNA-Seq data. Additionally, we observed more than 5-fold upregulation of several genes associated with neuroprotection, including insulin-like growth factor 2 and brain-derived neurotrophic factor. Conclusions: Results suggest that pericyte influence on blood-brain barrier endothelial gene expression confers protection from insulin resistance, iron accumulation, oxidative stress, and amyloid deposition. Since these are conditions associated with AD pathophysiology, they imply mechanisms by which pericyte degeneration could contribute to disease progression. Show more
Keywords: Alzheimer’s disease, blood-brain barrier, cerebrovascular dysfunction, computational biology, endothelial cells, pericytes
DOI: 10.3233/JAD-230907
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 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: 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: 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: Gordon, Scott | Lee, Jong Soo | Scott, Tammy M. | Bhupathiraju, Shilpa | Ordovas, Jose | Kelly, Rachel S. | Tucker, Katherine L. | Palacios, Natalia
Article Type: Research Article
Abstract: Background: Recent studies have identified plasma metabolites associated with cognitive decline and Alzheimer’s disease; however, little research on this topic has been conducted in Latinos, especially Puerto Ricans. Objective: This study aims to add to the growing body of metabolomics research in Latinos to better understand and improve the health of this population. Methods: We assessed the association between plasma metabolites and global cognition over 12 years of follow-up in 736 participants of the Boston Puerto Rican Health Study (BPRHS). Metabolites were measured with untargeted metabolomic profiling (Metabolon, Inc) at baseline. We used covariable adjusted linear …mixed models (LMM) with a metabolite * time interaction term to identify metabolites (of 621 measured) associated with ∼12 years cognitive trajectory. Results: We observed strong inverse associations between medium-chain fatty acids, caproic acid, and the dicarboxylic acids, azelaic and sebacic acid, and global cognition. N-formylphenylalanine, a tyrosine pathway metabolite, was associated with improvement in cognitive trajectory. Conclusions: The metabolites identified in this study are generally consistent with prior literature and highlight a role medium chain fatty acid and tyrosine metabolism in cognitive decline. Show more
Keywords: Alzheimer’s disease, cognitive decline, Latinos, metabolomics, Puerto rican
DOI: 10.3233/JAD-230053
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Das, Sudeshna
Article Type: Introduction
DOI: 10.3233/JAD-240272
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2024
Authors: Um, Yoo Hyun | Wang, Sheng-Min | Kang, Dong Woo | Kim, Sunghwan | Lee, Chang Uk | Kim, Donghyeon | Choe, Yeong Sim | Kim, Regina E.Y. | Lee, Soyoung | Lee, Min-Kyung | Lim, Hyun Kook
Article Type: Research Article
Abstract: Background: Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer’s disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4 ). Objective: This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-β (Aβ) deposition. Methods: A cohort of 112 cognitively intact individuals, all Aβ-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC …discrepancies between APOE4 statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aβ deposition on LC FC values. Results: The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers. Conclusions: These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aβ deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies. Show more
Keywords: Alzheimer’s disease, apolipoprotein E4, functional connectivity, locus coeruleus, preclinical
DOI: 10.3233/JAD-240065
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: García-Carlos, Carlos Antonio | Basurto-Islas, Gustavo | Perry, George | Mondragón-Rodríguez, Siddhartha
Article Type: Research Article
Abstract: Background: Cognitive deficits observed in Alzheimer’s disease (AD) patients have been correlated with altered hippocampal activity. Although the mechanism remains under extensive study, neurofibrillary tangles and amyloid plaques have been proposed as responsible for brain activity alterations. Aiming to unveil the mechanism, researchers have developed several transgenic models of AD. Nevertheless, the variability in hippocampal oscillatory alterations found in different genetic backgrounds and ages remains unclear. Objective: To assess the oscillatory alterations in relation to animal developmental age and protein inclusion, amyloid-β (Aβ) load, and abnormally phosphorylated tau (pTau), we reviewed and analyzed the published data on peak …power, frequency, and quantification of theta-gamma cross-frequency coupling (modulation index values). Methods: To ensure that the search was as current as possible, a systematic review was conducted to locate and abstract all studies published from January 2000 to February 2023 that involved in vivo hippocampal local field potential recording in transgenic mouse models of AD. Results: The presence of Aβ was associated with electrophysiological alterations that are mainly reflected in power increases, frequency decreases, and lower modulation index values. Concomitantly, pTau accumulation was associated with electrophysiological alterations that are mainly reflected in power decreases, frequency decreases, and no significant alterations in modulation index values. Conclusions: In this study, we showed that electrophysiological parameters are altered from prodromal stages to the late stages of pathology. Thus, we found that Aβ deposition is associated with brain network hyperexcitability, whereas pTau deposition mainly leads to brain network hypoexcitability in transgenic models Show more
Keywords: Alzheimer’s disease, amyloid-β, cross-frequency coupling, hippocampus, network hyperexcitability, network hypoexcitability, oscillatory activity, phospho-tau
DOI: 10.3233/JAD-231365
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Scharf, Annelie | Kleinke, Fabian | Michalowsky, Bernhard | Rädke, Anika | Pfitzner, Stefanie | Mühlichen, Franka | Buchholz, Maresa | van den Berg, Neeltje | Hoffmann, Wolfgang
Article Type: Research Article
Abstract: Background: The healthcare needs of People living with Dementia (PlwD) (such as Alzheimer’s disease) are often unmet. Information about the needs of community-dwelling PlwD and their association with sociodemographic and clinical characteristics is needed to fill the knowledge gap regarding factors influencing unmet needs among PlwD and to conduct a comprehensive needs assessment to develop tailored interventions. Objective: To describe sociodemographic and clinical characteristics of the InDePendent study population with particular reference to determinants of unmet needs. Methods: We analyzed baseline data of the multi-centre cluster-randomized controlled trial (InDePendent) using descriptive statistics to describe patients’ sociodemographic …and clinical characteristics and Poisson regression models to predict unmet needs, separated by sex. Data were collected personally via face-to-face interviews. Results: Most of the n = 417 participating PlwD were mild to moderately cognitively impaired, were not depressed, had an average of 10.8 diagnoses, took 6.7 medications, and had, on average, 2.4 unmet needs (62% of PlwD had at least one unmet need) measured by the Camberwell Assessment of Need for the Elderly (CANE). Low social support, a high body-mass-index, a lower education, functional impairment, and worse health status were associated with more unmet needs, regardless of sex. In women, higher unmet needs were associated with more depressive symptoms, a poor financial situation, living alone and not being recently treated by a general practitioner. In males, unmet needs increased with the number of medications taken. Conclusions: PlwD had a broad array of unmet healthcare needs, indicating primary healthcare provision improvement potentials. The results underscore the significance of early assessment of patient’s clinical characteristics and unmet needs as a basis for individualized gender-sensible intervention strategies.∥ClinicalTrials.gov Identifier: NCT04741932, Registered on February 5, 2021 Show more
Keywords: KeywordsAlzheimer’s disease, Camberwell Assessment of Need for the Elderly (CANE), dementia, elderly population, health services research, needs assessment, people with dementia, primary care, randomized controlled trial
DOI: 10.3233/JAD-231173
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Miller, Morgan R. | Lariviere, Lavender | Pagnier, Guillaume J. | Aygar, Sema | Wieckiewic, Natalia | Maesako, Masato | Bacskai, Brian J. | Kastanenka, Ksenia V.
Article Type: Short Communication
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease with limited therapeutic strategies. NB-02 is a novel botanical drug that has shown promise as a protective and therapeutic treatment for AD in an APP/PS1 preclinical mouse model. In this paper, we investigate the underlying mechanisms by which NB-02 provides these therapeutic advantages using in vitro neuron-astrocyte co-cultures. Pretreatment with NB-02 prevented pathological calcium elevations in neurons and astrocytes after application of toxic soluble amyloid-β (Aβ) oligomers. NB-02 also prevented cell death associated with the addition of soluble Aβ oligomers suggesting NB-02 is effective at protecting both neurons and astrocytes from …Aβ-mediated damage. Show more
Keywords: Alzheimer’s disease, amyloid, astrocyte, calcium, DA-9803, NB-02, neuron, oligomer, therapy
DOI: 10.3233/JAD-231387
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2024
Authors: Liu, Mengqing | Ma, Nenghong | Yang, Xiao | Sun, Miao | Li, Xiaowen | Liu, Yuhui | Chang, Qing | Hei, Changchun
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is released in response to nutrient intake. It plays a role in maintaining metabolic homeostasis and has been suggested to be involved in maintaining the brain microenvironment. However, the role of GLP-1 in AD pathogenesis has not been fully illustrated. Objective: This study aims to investigate the clinical relevance of GLP-1 in AD and the effects of GLP-1 in amyloid-β (Aβ) metabolism in vitro . …Methods: In this study, 39 AD patients and 120 cognitively intact controls were included. Plasma levels of GLP-1 were measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) were treated with GLP-1. Western blot analysis was used to assess the effects of GLP-1 on the metabolism of Aβ. Results: Plasma GLP-1 levels were decreased with aging. Plasma GLP-1 levels were lower in AD patients in comparison with healthy older adults. Plasma GLP-1 levels were positively associated with Mini-Mental State Examination scores but negatively associated with plasma pTau181 levels. GLP-1 dose-dependently increased the area fraction of mitochondrial staining in vitro . Furthermore, GLP-1 dose-dependently promoted the α-cleavage of APP, thus reducing the generation of Aβ. Conclusions: GLP-1 has neuroprotective effects in AD, and therefore the decrease in GLP-1 levels during aging might contribute to the development of AD. Show more
Keywords: Aging, Alzheimer’s disease, amyloid-β, glucagon-like peptide-1 (GLP-1), tau protein phosphorylation
DOI: 10.3233/JAD-240001
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-09, 2024
Authors: Libard, Sylwia | Hodik, Monika | Cesarini, Kristina Giuliana | Dragomir, Anca | Alafuzoff, Irina
Article Type: Research Article
Abstract: Background: Amyloid-β (Aβ) is one of the hallmark lesions of Alzheimer’s disease (AD). During the disease process, Aβ undergoes biochemical changes, producing toxic Aβ variants, proposed to be detected within the neurons. Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive impairment, gait, and urinary symptoms in elderly, that can be reversed by a ventriculo-peritoneal shunt. Majority of iNPH subjects display different Aβ variants in their brain biopsies, obtained during shunting. Objective: To study the cellular compartmentalization of different Aβ variants in brain biopsies from iNPH subjects. Methods: We studied the cellular localization of different …proteoforms of Aβ using antibodies towards different amino acid sequences or post-translational modifications of Aβ, including clones 4G8, 6F/3D, unmodified- (7H3D6), pyroglutamylated- (N3pE), phosphorylated-(1E4E11) Aβ and Aβ protein precursor (AβPP), in brain biopsies from 3 iNPH subjects, using immunohistochemistry and light microscopy (LM), light microscopy on semi-thin sections (LMst), and electron microscopy (EM). Results: In LM all Aβ variants were detected. In LMst and EM, the Aβ 4G8, 6F/3D, and the pyroglutamylated Aβ were detected. The AβPP was visualized by all methods. The Aβ labelling was located extracellularly with no specific signal within the intracellular compartment, whereas the AβPP was seen both intra- and extracellularly. Conclusions: The Aβ markers displayed extracellular localization when visualized by three assessment techniques, reflecting the pathological extracellular accumulation of Aβ in the human brain. No intracellular Aβ pathology was seen. AβPP was visualized in intra- and extracellularly, which corresponds to the localization of the protein in the membranes of cells and organelles. Show more
Keywords: Alzheimer’s disease, Alzheimer’s disease neuropathological change, amyloid-β, idiopathic normal pressure hydrocephalus
DOI: 10.3233/JAD-240167
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Duran, Tugce | Gaussoin, Sarah A. | Latham, Lauren A. | Rundle, Melissa M. | Espeland, Mark A. | Williams, Benjamin J. | Hughes, Timothy M. | Craft, Suzanne | Sachs, Bonnie C. | Bateman, James R. | Lockhart, Samuel N.
Article Type: Research Article
Abstract: Background: The preclinical Alzheimer’s cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone or video administration. It is desirable to have a harmonized composite measurement derived from both in-person and remote assessments for identifying cognitive changes and to examine its relationship with common neuroimaging biomarkers. Objective: We defined a telehealth compatible PACC (tPACC) and examined its relationship with neuroimaging biomarkers related to neurodegeneration, brain function and perfusion, white matter integrity, and amyloid-β. Methods: We …examined 648 participants’ neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core cohort (observational study) to calculate a modified PACC (PACC5-RAVLT) score and tPACC scores (in-person and remote). We performed Spearman/intraclass correlation coefficient (ICC) analyses for reliability of tPACC scores and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal and impaired (mild cognitive impairment and dementia) participants. Results: There was a significant positive relationship between tPACCin - person and PACC5-RAVLT (Overall group: r2 = 0.94, N = 648), and tPACCin - person and tPACCremote (validation subgroup: ICC = 0.82, n = 53). Overall, tPACC showed significant associations with brain thickness/volume, gray matter perfusion, white matter free water, and amyloid-β deposition. Conclusions: There is a good agreement between tPACCand PACC5-RAVLTfor cognitively normal and impaired individuals. The tPACC is associated with common neuroimaging markers of Alzheimer’s disease. Show more
Keywords: Alzheimer’s disease, amyloid-beta, cognitive composite, cognitive decline, MRI, PET, reliability, telehealth testing
DOI: 10.3233/JAD-231435
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Bulycheva, Irina | Watanabe, Yumi | Kitamura, Kaori | Kabasawa, Keiko | Saito, Toshiko | Takahashi, Akemi | Kobayashi, Ryosaku | Oshiki, Rieko | Takachi, Ribeka | Tsugane, Shoichiro | Yamazaki, Osamu | Watanabe, Kei | Nakamura, Kazutoshi
Article Type: Research Article
Abstract: Background: Sleep is a potentially modifiable factor associated with dementia, including Alzheimer’s disease, but current evidence supporting this is insufficient. Objective: This study aimed to determine whether sleep duration and bedtime patterns are associated with the risk of dementia among middle-aged and older people. Methods: This cohort study had an eight-year follow-up period. Participants were 13,601 community-dwelling people aged 40–74 years living in Murakami (Niigata, Japan). Data were collected using a self-administered questionnaire. Predictors were self-reported sleep duration and bedtime, and the outcome was newly-diagnosed dementia determined using the long-term care insurance database. Covariates were demographic …characteristics, body mass index, smoking, alcohol consumption, total physical activity, insomnia symptoms, disease history, and either bedtime or sleep duration. Cox proportional hazard models were used to calculate hazard ratios (HRs). Results: The mean age of participants at baseline was 59.2 years. Over a mean follow-up period of 8.0 years, 319 cases of dementia were observed. A long self-reported sleep duration relative to the reference sleep duration (7 hours) was associated with increased dementia risk, with the “8 hours” group (adjusted HR = 1.30, 95% CI:0.99–1.73) and “≥9 hours” group (adjusted HR = 1.46, 95% CI:1.00–2.15) having an increased risk (marginally significant) relative to the reference group. Early bedtime was associated with increased dementia risk (adjusted p for trend = 0.0010), with the “21 : 00 or earlier” group (adjusted HR = 1.61, 95% CI:1.14–2.28) having an increased risk relative to the reference (“23 : 00”). Conclusions: A long self-reported sleep duration and early bedtime are both associated with increased dementia risk in middle-aged and older people Show more
Keywords: Alzheimer’s disease, bedtime, cohort study, dementia, sleep duration
DOI: 10.3233/JAD-231104
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Liu, Jiaqi | Sun, Sirui | Chen, Yongjie
Article Type: Research Article
Abstract: Background: Numerous studies have investigated the correlation between malondialdehyde (MDA) and cognitive decline. However, limited research has explored the interplay between superoxide dismutase (SOD), C-reactive protein (CRP), and MDA. Objective: This study aims to scrutinize the association between MDA and cognitive function in older adults, while also elucidating the roles of SOD and CRP within this relationship. Methods: Utilizing data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) spanning 2008–2009, 2011–2012, and 2014, this study included 2,696 eligible subjects. Cognitive function was evaluated using the Chinese version of the Mini-Mental State Examination (MMSE). Linear mixed-effects models …were employed to examine the links between MDA, SOD, CRP, and their interactions with cognitive function. Results: Elevated serum levels of MDA and CRP, as well as decreased serum SOD levels, were related to decreased cognitive function (β= –0.220 and –0.346, 95% CI: –0.399, –0.041 and –0.526, –0.167 for MDA and CRP; β= 0.384, 95% CI: 0.204, 0.564 for SOD). Notably, a significant interaction between MDA and SOD was detected (p = 0.001). An increase per standard deviation in serum MDA levels was significantly associated with a 0.347-point lower MMSE score only in participants with normal cognitive function and high SOD levels (β= –0.347, 95% CI: –0.497, –0.197; p < 0.001). Conclusions: Elevated serum MDA levels in the normal population with high SOD levels suggested diminished cognitive performance. Combining MDA with SOD could be pivotal in identifying older adults at risk of cognitive decline in clinical settings. Show more
Keywords: Alzheimer’s disease, cognitive decline, C-reactive protein malondialdehyde, mini-mental state examination score, superoxide dismutase
DOI: 10.3233/JAD-231278
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Thunell, Johanna A. | Joyce, Geoffrey F. | Ferido, Patricia M. | Chen, Yi | Guadamuz, Jenny S. | Qato, Dima M. | Zissimopoulos, Julie M.
Article Type: Research Article
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) and prescribed central nervous system (CNS) active drugs to treat them are prevalent among persons living with Alzheimer’s disease and related dementias (PLWD) and lead to negative outcomes for PLWD and their caregivers. Yet, little is known about racial/ethnic disparities in diagnosis and use of drugs to treat BPSD. Objective: Quantify racial/ethnic disparities in BPSD diagnoses and CNS-active drug use among community-dwelling PLWD. Methods: We used a retrospective cohort of community-dwelling Medicare Fee-for-Service beneficiaries with dementia, continuously enrolled in Parts A, B and D, 2017–2019. Multivariate logistic models …estimated rates of BPSD diagnosis and, conditional on diagnosis, CNS-active drug use. Results: Among PLWD, 67.1% had diagnoses of an affective, psychosis or hyperactivity symptom. White (68.3%) and Hispanic (63.9%) PLWD were most likely, Blacks (56.6%) and Asians (52.7%) least likely, to have diagnoses. Among PLWD with BPSD diagnoses, 78.6% took a CNS-active drug. Use was highest among whites (79.3%) and Hispanics (76.2%) and lowest among Blacks (70.8%) and Asians (69.3%). Racial/ethnic differences in affective disorders were pronounced, 56.8% of white PLWD diagnosed; Asians had the lowest rates (37.8%). Similar differences were found in use of antidepressants. Conclusions: BPSD diagnoses and CNS-active drug use were common in our study. Lower rates of BPSD diagnoses in non-white compared to white populations may indicate underdiagnosis in clinical settings of treatable conditions. Clinicians’ review of prescriptions in this population to reduce poor outcomes is important as is informing care partners on the risks/benefits of using CNS-active drugs. Show more
Keywords: Alzheimer’s disease, antidepressants, antipsychotics, behavioral and psychological symptoms of dementia, dementia
DOI: 10.3233/JAD-231266
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Elghanam, Yomna | Purja, Sujata | Kim, Eun Young
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that imposes economic and societal burden. Biomarkers have played a crucial role in the recent approval of aducanumab and lecanemab as disease-modifying therapies which marked a significant milestone for the treatment of AD. The inclusion of biomarkers in AD trials facilitates precise diagnosis, monitors safety, demonstrates target engagement, and supports disease modification. Objective: This study analyzed the utilization state and trends of biomarkers as endpoints in AD trials. Methods: In this retrospective study, trials were collected by searching clinicaltrials.gov using the term “Alzheimer”. Primary and …secondary outcomes were analyzed separately for each phase. Results: Among the 1,048 analyzed trials, 313 (29.87%) adopted biomarkers as primary endpoints and 364 (34.73%) as secondary endpoints, mainly in phases 1 and 2. The top three biomarkers adopted as primary endpoints in phases 1, 2, and 3 were amyloid-PET, tau-PET, and MRI. The top three biomarkers adopted as secondary endpoints, in phase 1, were cerebrospinal fluid (CSF) amyloid-β (Aβ), blood Aβ and amyloid-PET; in phase 2, they were MRI, CSF Aβ, and CSF phospho-tau; and in phase 3, they were amyloid PET, MRI, and blood Aβ. There was a statistically significant increase in the adoption of biomarkers as primary endpoints in phase 2 trials (p = 0.001) and secondary endpoints in phase 3 trials (p = 0.001). Conclusions: The growing recognition of the importance of biomarkers in AD trial’ design and drug development is evident by the significant steady increase in biomarkers’ utilization in phases 2 and 3. Show more
Keywords: Alzheimer’s disease, amyloid, biomarkers, clinical trials, drug development, endpoint, tau
DOI: 10.3233/JAD-240008
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Memon, Ashar | Moore, Jasmine A. | Kang, Chris | Ismail, Zahinoor | Forkert , Nils D.
Article Type: Research Article
Abstract: Background: While various biomarkers of Alzheimer’s disease (AD) have been associated with general cognitive function, their association to visual-perceptive function across the AD spectrum warrant more attention due to its significant impact on quality of life. Thus, this study explores how AD biomarkers are associated with decline in this cognitive domain. Objective: To explore associations between various fluid and imaging biomarkers and visual-based cognitive assessments in participants across the AD spectrum. Methods: Data from participants (N = 1,460) in the Alzheimer’s Disease Neuroimaging Initiative were analyzed, including fluid and imaging biomarkers. Along with the Mini-Mental State Examination …(MMSE), three specific visual-based cognitive tests were investigated: Trail Making Test (TMT) A and TMT B, and the Boston Naming Test (BNT). Locally estimated scatterplot smoothing curves and Pearson correlation coefficients were used to examine associations. Results: MMSE showed the strongest correlations with most biomarkers, followed by TMT-B. The p-tau181/Aβ1–42 ratio, along with the volume of the hippocampus and entorhinal cortex, had the strongest associations among the biomarkers. Conclusions: Several biomarkers are associated with visual processing across the disease spectrum, emphasizing their potential in assessing disease severity and contributing to progression models of visual function and cognition. Show more
Keywords: Alzheimer’s disease, biomarkers, dementia, MRI, neuroimaging, visual processing
DOI: 10.3233/JAD-231084
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Xu, Feifan | Xu, Jiajie | Wang, Qiong | Gao, Feng | Fu, Jiayu | Yan, Tingmeng | Dong, Qiang | Su, Ya | Cheng, Xin
Article Type: Research Article
Abstract: Background: Neuroinflammation is a major cause of secondary brain injury in intracerebral hemorrhage (ICH). To date, the prognostic value of YKL-40 (chitinase-3-like-1 protein), a biomarker of neuroinflammation, in cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-ICH) remains undiscovered. Objective: To evaluate the relationships between serum YKL-40 and CAA-ICH recurrence. Methods: Clinical and imaging information of 68 first-onset probable CAA-ICH cases and 95 controls were collected at baseline. Serum YKL-40 was measured by Luminex assay. Cox proportional hazards model was used to analyze the associations between YKL-40 level and CAA-ICH recurrence. Results: Serum YKL-40 level was significantly …higher in CAA-ICH cases than healthy controls (median [interquartile range, IQR], 46.1 [19.8, 93.4] versus 24.4 [13.9, 59.0] ng/mL, p = 0.004). Higher level of YKL-40 predicted increased risk of CAA-ICH recurrence adjusted for age, ICH volume and enlarged perivascular space score (ePVS) (above versus below 115.5 ng/ml, adjusted hazard ratios 4.721, 95% confidence intervals 1.829–12.189, p = 0.001) within a median follow-up period of 2.4 years. Adding YKL-40 to a model of only MRI imaging markers including ICH volume and ePVS score improved the discriminatory power (concordance index from 0.707 to 0.772, p = 0.001) and the reclassification power (net reclassification improvement 28.4%; integrated discrimination index 11.0%). Conclusions: Serum YKL-40 level might be a candidate prognostic biomarker for CAA-ICH recurrence. Show more
Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, intracerebral hemorrhage, recurrence, YKL-40
DOI: 10.3233/JAD-231125
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Huang, Zhen
Article Type: Review Article
Abstract: Mounting evidence indicates that a physiological function of amyloid-β (Aβ) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized the lines of evidence supporting this hypothesis and highlighted the similarities between Aβ and anti-microbial peptides in mediating cell/synapse competition. In cell competition, anti-microbial peptides deploy a multitude of mechanisms to ensure both self-protection and competitor elimination. Here I review recent studies showing that similar mechanisms are at play in Aβ-mediated synapse competition and perturbations in these mechanisms underpin Alzheimer’s disease (AD). Specifically, I discuss evidence that Aβ and ApoE, two crucial players …in AD, co-operate in the regulation of synapse competition. Glial ApoE promotes self-protection by increasing the production of trophic monomeric Aβ and inhibiting its assembly into toxic oligomers. Conversely, Aβ oligomers, once assembled, promote the elimination of competitor synapses via direct toxic activity and amplification of “eat-me” signals promoting the elimination of weak synapses. I further summarize evidence that neuronal ApoE may be part of a gene regulatory network that normally promotes competitive plasticity, explaining the selective vulnerability of ApoE expressing neurons in AD brains. Lastly, I discuss evidence that sleep may be key to Aβ-orchestrated plasticity, in which sleep is not only induced by Aβ but is also required for Aβ-mediated plasticity, underlining the link between sleep and AD. Together, these results strongly argue that AD is a disease of competitive synaptic plasticity gone awry, a novel perspective that may promote AD research. Show more
Keywords: Alzheimer’s disease, amyloid-β, ApoE, dendritic spine, DNA damage repair, homeostatic plasticity, mGluR5, phosphatidylserine, sleep, synaptic competition
DOI: 10.3233/JAD-240042
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2024
Authors: Gaster, Barak | Suchsland, Monica Zigman | Fitzpatrick, Annette L. | Liao, Joshua M. | Belza, Basia | Hsu, Amy P. | McKiddy, Sarah | Park, Christina | Olivari, Benjamin S. | Singh, Angad P. | Raetz, Jaqueline
Article Type: Research Article
Abstract: Background: The prevalence of Alzheimer’s disease and related disorders (ADRD) is rising. Primary care providers (PCPs) will increasingly be required to play a role in its detection but lack the training to do so. Objective: To develop a model for cognitive evaluation which is feasible in primary care and evaluate its implementation in a large health system. Methods: The Cognition in Primary Care Program consists of web-based training together with integrated tools built into the electronic record. We implemented the program among PCPs at 14 clinics in a large health system. We (1) surveyed PCPs to …assess the impact of training on their confidence to evaluate cognition, (2) measured the number of cognitive assessments they performed, and (3) tracked the number of patients diagnosed with mild cognitive impairment (MCI). Results: Thirty-nine PCPs completed the training which covered how to evaluate cognition. Survey response rate from those PCPs was 74%. Six months after the end of the training, they reported confidence in assessing cognition (mean 4.6 on 5-point scale). Cognitive assessments documented in the health record increased from 0.8 per month before the training to 2.5 in the six months after the training. Patients who were newly diagnosed with MCI increased from 4.2 per month before the training to 6.0 per month in the six months after the training. Conclusions: This model for cognitive evaluation in a large health system was shown to increase cognitive testing and increase diagnoses of MCI. Such improvements are essential for the timely detection of ADRD. Show more
Keywords: Alzheimer’s disease, cognitive dysfunction, continuing medical education, dementia, early detection of disease, mild cognitive impairment, primary care
DOI: 10.3233/JAD-231200
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Wu, Bin | Chen, Mulan | Meng, Ling | Tian, Qiuyun | Dong, Zhifang
Article Type: Research Article
Abstract: Background: The amyloid-β (Aβ) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of developing dementia or Alzheimer’s disease (AD). Despite this association, the contribution of bone-resorbing OCs to the progression of AD pathology remains unclear. Objective: Our objective was to investigate the potential impacts of OCs on the development of AD pathology. Methods: We conducted targeted analysis of publicly available whole blood transcriptomes from patients with AD to characterize the blood molecular signatures and pathways associated with hyperactive OCs. In addition, we used APP23 transgenic (APP23 …TG) AD mouse model to assess the effects of OCs pharmacological blockade on AD pathology and behavior. Results: Patients with AD exhibited increased osteoclastogenesis signature in their blood cells, which appears to be positively correlated with dysfunction of peripheral clearance of Aβ mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aβ-degrading enzyme expression, Aβ-deposition, and memory decline. Conclusions: Our findings suggest that OCs have a disease-promoting role in the development and progression of AD, possibly linked to their modulation of peripheral immunity. These findings guide future research to further elucidate the connection between OP and AD pathogenesis, highlighting the potential benefits of preventing OP in alleviating cognitive burden. Show more
Keywords: Alzheimer’s disease, amyloid-β burden, monocyte, osteoclast, osteoporosis
DOI: 10.3233/JAD-240096
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Asada, Takashi | Tanaka, Mieko | Araki, Wataru | Jon Lebowitz, Adam | Kakuma, Tatsuyuki
Article Type: Research Article
Abstract: Background: Interventions to prevent or attenuate cognitive decline and dementia in older adults are becoming increasingly important. Recently, cognitive training exercise can be via computer or mobile technology for independent or home use. Recent meta-analysis has reported that Computerized Cognitive Training (CCT) is effective at enhancing cognitive function in healthy older and Alzheimer’s disease adults, although little is known about individual characteristics of each computerized program. Objective: We developed a new CCT named Brain Training Based on Everyday Living (BTEL) to enhance cognitive capacity for Instrumental Activities of Daily Living (IADL). We aim to evaluate the efficacy of …the BTEL among cognitively healthy old individuals and to explore its concurrent validity and construct concept. Methods: We conducted a double-blind study where 106 individuals aged 65 years and older (intervened = 53, control = 53) worked on the active and placebo tasks three times a week over three months (clinical trial: UMIN000048730). The main results were examined using ANCOVA and calculating correlation coefficients. Results: We found no effect on total score of the three tests; however, there was significant effect for the BTEL on: recognition in MMSE, and immediate recall in HDSR. The tasks are associated with prefrontal cortex. In addition, correlations indicated that each BTEL domain had some validity as a cognitive assessment tool. Different from previous CCT, we determined the neuropsychological characteristics of specific cognitive tasks of the BTEL to a certain degree. Conclusions: We found modest efficacy of the BTEL in cognitively healthy old individuals and confirmed its concurrent validity and the conceptual construct. Show more
Keywords: Activities of daily living, Alzheimer’s disease, brain training, mild cognitive impairment, neuropsychology
DOI: 10.3233/JAD-231165
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: de Oliveira, Fabricio Ferreira
Article Type: Article Commentary
Abstract: Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer’s disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer’s disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits.
Keywords: Alzheimer’s disease, amyloidosis, APOE , biomarkers, dementia, hypertension, renin-angiotensin system, tau proteins
DOI: 10.3233/JAD-240032
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Ohno, Masuo
Article Type: Review Article
Abstract: Given continued failure of BACE1 inhibitor programs at symptomatic and prodromal stages of Alzheimer’s disease (AD), clinical trials need to target the earlier preclinical stage. However, trial design is complex in this population with negative diagnosis of classical hippocampal amnesia on standard memory tests. Besides recent advances in brain imaging, electroencephalogram, and fluid-based biomarkers, new cognitive markers should be established for earlier diagnosis that can optimize recruitment to BACE1 inhibitor trials in presymptomatic AD. Notably, accelerated long-term forgetting (ALF) is emerging as a sensitive cognitive measure that can discriminate between asymptomatic individuals with high risks for developing AD and healthy …controls. ALF is a form of declarative memory impairment characterized by increased forgetting rates over longer delays (days to months) despite normal storage within the standard delays of testing (20–60 min). Therefore, ALF may represent a harbinger of preclinical dementia and the impairment of systems memory consolidation, during which memory traces temporarily stored in the hippocampus become gradually integrated into cortical networks. This review provides an overview of the utility of ALF in a rational design of next-generation BACE1 inhibitor trials in preclinical AD. I explore potential mechanisms underlying ALF and relevant early-stage biomarkers useful for BACE1 inhibitor evaluation, including synaptic protein alterations, astrocytic dysregulation and neuron hyperactivity in the hippocampal-cortical network. Furthermore, given the physiological role of the isoform BACE2 as an AD-suppressor gene, I also discuss the possible association between the poor selectivity of BACE1 inhibitors and their side effects (e.g., cognitive worsening) in prior clinical trials. Show more
Keywords: Accelerated long-term forgetting, Alzheimer’s disease, amyloid-β , BACE1 inhibitors, BACE2, biomarkers, clinical trials, mouse models, preclinical stage, side effects
DOI: 10.3233/JAD-231451
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Georgescu, Michael F. | Beydoun, May A. | Ashe, Jason | Maino Vieytes, Christian A. | Beydoun, Hind A. | Evans, Michele K. | Zonderman, Alan B.
Article Type: Research Article
Abstract: Background: Loneliness, dementia, and mortality are interconnected. Objective: We aimed at understanding mediating pathways and interactions between loneliness and dementia in relation to mortality risk. Methods: The study tested bi-directional relationships between dementia, loneliness, and mortality, by examining both interactions and mediating effects in a large sample of older US adults participating in the nationally representative Health and Retirement Study. Out of≤6,468 older participants selected in 2010, with mean baseline age of 78.3 years and a follow-up time up to the end of 2020, 3,298 died at a rate of 64 per 1,000 person-years (P-Y). Cox …proportional hazards and four-way decomposition models were used. Results: Algorithmically defined dementia status (yes versus no) was consistently linked with a more than two-fold increase in mortality risk. Dementia status and Ln(odds of dementia) were strongly related with mortality risk across tertiles of loneliness score. Loneliness z-score was also linked to an elevated risk of all-cause mortality regardless of age, sex, or race or ethnicity, and its total effect (TE) on mortality was partially mediated by Ln(odds of dementia), z-scored, (≤40% of the TE was a pure indirect effect). Conversely, a small proportion (<5% ) of the TE of Ln (odds of dementia), z-scored, on mortality risk was explained by the loneliness z-score. Conclusions: In sum, dementia was positively associated with all-cause mortality risk, in similar fashion across loneliness score tertiles, while loneliness was associated with mortality risk. TE of loneliness on mortality risk was partially mediated by dementia odds in reduced models. Show more
Keywords: Aging, Alzheimer’s disease, cohort studies, dementia, loneliness, mortality
DOI: 10.3233/JAD-231359
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Li, Yaoru | Yang, Ziying | Zhang, Yanxin | Liu, Fang | Xu, Jing | Meng, Yaping | Xing, Gebeili | Ruan, Xuqin | Sun, Jun | Zhang, Nan
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or …likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO , and DCTN1 , were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases. Show more
Keywords: Alzheimer’s disease, frontotemporal lobar degeneration, variant, whole-exome sequencing
DOI: 10.3233/JAD-231361
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Chu, Yili | Xie, Qihui | Meng, Rongrong | Leng, Bing | Cao, Zhenxiang
Article Type: Research Article
Abstract: Background: With the increasing popularity of the internet, a growing number of patients and their companions are actively seeking health-related information online. Objective: The aim of this study was to assess the quality and readability of online information about Alzheimer’s disease (AD) in China. Methods: A total of 263 qualified AD-related web pages from different businesses, governments, and hospitals were obtained. The quality of the web pages was assessed using the DISCERN tool, and the readability of the web pages was assessed using a readability measurement website suitable for the Chinese language. The differences in readability …and quality between different types of web pages were investigated, and the correlation between quality and readability was analyzed. Results: The mean overall DISCERN score was 40.93±7.5. The government group scored significantly higher than the commercial and hospital groups. The mean readability score was 12.74±1.27, and the commercial group had the lowest readability score. There was a positive correlation between DISCERN scores and readability scores. Conclusions: This study presents an evaluation of the quality and readability of health information pertaining to AD in China. The findings indicate that there is a need to enhance the quality and readability of web pages about AD in China. Recommendations for improvement are proposed in light of these findings. Show more
Keywords: Alzheimer’s disease, internet, quality evaluation, readability evaluation
DOI: 10.3233/JAD-231339
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Gale, Seth A.
Article Type: Article Commentary
Abstract: As the biological, biomarker-driven framework of Alzheimer’s disease (AD) becomes formalized through revised, consensus clinical criteria, clinicians will confront more and more patients in the earliest, asymptomatic stages of disease. The language and diction used by practitioners to characterize these early patients, whether they are diagnosed with AD, and how their condition is documented in medical and legal records have important implications for both their care and their medical-legal status outside of the health system. Investigation is needed urgently to better understand clinicians’ views and practices regarding early AD, as we adapt to new disease definitions in this unprecedented era …of care. Show more
Keywords: Alzheimer’s disease, asymptomatic Alzheimer’s disease, biomarkers, data privacy, language, legal liability, medical law, nosology, preclinical Alzheimer’s disease
DOI: 10.3233/JAD-240195
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Horvath, Alexandra | Quinlan, Patrick | Eckerström, Carl | Åberg, N. David | Wallin, Anders | Svensson, Johan
Article Type: Research Article
Abstract: Background: Insulin-like growth factor-I (IGF-I) regulates myelin, but little is known whether IGF-I associates with white matter functions in subjective and objective mild cognitive impairment (SCI/MCI) or Alzheimer’s disease (AD). Objective: To explore whether serum IGF-I is associated with magnetic resonance imaging – estimated brain white matter volumes or cognitive functions. Methods: In a prospective study of SCI/MCI (n = 106) and AD (n = 59), we evaluated the volumes of the total white matter, corpus callosum (CC), and white matter hyperintensities (WMHs) as well as Mini-Mental State Examination (MMSE), Trail Making Test A and B (TMT-A/B), and …Stroop tests I–III at baseline, and after 2 years. Results: IGF-I was comparable in SCI/MCI and AD (113 versus 118 ng/mL, p = 0.44). In SCI/MCI patients, the correlations between higher baseline IGF-I and greater baseline and 2-year volumes of the total white matter and total CC lost statistical significance after adjustment for intracranial volume and other covariates. However, after adjustment for covariates, higher baseline IGF-I correlated with better baseline scores of MMSE and Stroop test II in SCI/MCI and with better baseline results of TMT-B and Stroop test I in AD. IGF-I did not correlate with WMH volumes or changes in any of the variables. Conclusions: Both in SCI/MCI and AD, higher IGF-I was associated with better attention/executive functions at baseline after adjustment for covariates. Furthermore, the baseline associations between IGF-I and neuropsychological test results in AD may argue against significant IGF-I resistance in the AD brain. Show more
Keywords: Alzheimer’s disease, attention, corpus callosum, executive function, insulin-like growth factor-I, magnetic resonance imaging, mild cognitive impairment, speed, subjective mild cognitive impairment, white matter hyperintensities
DOI: 10.3233/JAD-231026
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
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