bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome‐wide association study for Alzheimer disease in APOE ɛ4/ɛ4 carriers
Authors: Clayton Samantha , Goldstein Daniel , Wang Li‐San , Mayeux Richard , Haines Jonathan L. , Pericak‐Vance Margaret A. , Schellenberg Gerald D. , Lunetta Kathryn L. , Au Rhoda , Farrer Lindsay A. , Stein Thor D. , Jun Gyungah R 
Published: December 2023

AbstractBackgroundThe APOE ɛ4/ɛ4 genotype has the greatest risk for late‐onset Alzheimer disease (AD). However, modifying effects of other genes on AD risk in APOE ɛ4 homozygotes are not fully understood.MethodsWe conducted a genome‐wide association study (GWAS) for AD among 1,223 non‐Hispanic White APOE ɛ4/ɛ4 carriers assembled by the Alzheimer’s Disease Genetics Consortium (ADGC). Expression of genes within 50 kb of suggestively associated single nucleotide polymorphisms (SNPs, P<10−6) were compared between AD and control brains from 576 Religious Orders Study and Memory and Aging Project (ROSMAP) subjects. We conducted survival analysis between carriers and non‐carriers of AD risk alleles for the suggestive SNPs in 4,287 Framingham Heart Study (FHS) participants. We compared expression of the top‐ranked genes between ɛ2/ɛ2 (APOE2) and ɛ4/ɛ4 (APOE4) human induced pluripotent stem cells (iPSC)‐derived neurons (iNeurons) and astrocytes (iAstrocytes) in a co‐culture system (Jun et al, 2022) and separately evaluated associations of their expression levels with neuropathological traits from 208 brains from FHS participants.ResultsWe identified association of AD with 11 SNPs at the suggestive level of which four near TRIB2, CTNNA2, ZNF443, and KLHL29 were genome‐wide significant (P<5×10−8). Rs75983775 near TRIB2, the most significant finding (P = 9.4×10−11), was associated with decreased risk of AD in ADGC APOE ɛ4 homozygotes (odds ratio = 0.12) and increased TRIB2 expression in ROSMAP ɛ4‐carrier brains (P = 0.02). TRIB2 expression was increased in APOE2 compared to APOE4 iAstrocytes (log2 fold change (log2FC) = 0.41, adjusted P (adjP) = 0.03) and iNeurons (log2FC = 0.31, adjP = 0.002) and elevated the Iba1 level in FHS brains (P = 0.03). Association with TENM3 SNP rs56035906 was suggestively associated with reduced AD risk in ADGC APOE ɛ4 homozygotes (odds ratio = 0.30, P = 4.3×10−7) and with lower incidence of AD among FHS ɛ4 carriers (P = 0.03). TENM3 expression was decreased in APOE2 compared to APOE4 iNeurons (log2FC = 0.59, adjP = 2.4×10−4) and associated with increasing phosphorylated tau 181 (P = 0.007) and C4a protein expression (P = 9.6×10−4) in FHS brains.ConclusionWe identified variants that may protect against AD risk among APOE ɛ4/ɛ4 carriers, delay disease onset, modulate expression of nearby genes in iAstrocytes and iNeurons, and are associated with measures of tau and neuroinflammation in autopsied brains.
Whole Genome Deconvolution Unveils Alzheimer’s Resilient Epigenetic Signature.
Authors: Berson Eloise 
Published: December 2023

AbstractBackgroundThe pathological hallmarks of Alzheimer’s disease (AD) are amyloid beta plaques and neurofibrillary tangles that usually progressively affect characteristic brain regions as individuals advance from latent to prodromal to severe AD dementia (ADD). An uncommon exception to coupled progression of disease burden and clinical impairment are resilient individuals who harbor a high pathological load sufficient to cause ADD yet remain cognitively normal. We hypothesize that determining the biological mechanisms of such underlying resilience to AD (RAD) will provide unique insights into therapeutic opportunities.MethodHere, we combined epigenetic sequencing data and an innovative computational algorithm to identify gene regulatory mechanisms and putative mediators distinguishing RAD from normal control and ADD at an unprecedented scale. We developed and validated a novel machine learning method, Cellformer, for deconvoluting bulk ATAC‐seq into cell type‐specific expression across the whole genome, leading to extensive regional and cellular chromatin profiling of RAD.ResultCellformer successfully deconvoluted in silico bulk ATAC‐seq data across cross‐validation iterations, achieving strong performances with a mean Spearman coefficient of 0.82 between deconvoluted and ground truth expressions, outperforming other approaches. Validation was performed using external single nucleus datasets and showed a significant correlation above 0.75 (P‐value<0.05) between deconvoluted cell type‐specific ATAC‐seq and single‐ATAC‐seq expressions for each cell type. Applied on 191 samples from normal control, RAD and ADD’s 3 brain regions, CellFormer predicted cell type‐specific expression of more than 41954 open chromatin regions (OCR), preserving regional and phenotypic variations. Downstream analysis of the derived RAD‐specific epigenetic features pinpointed the hippocampus, a region critical for learning and memory, as the major player in the resilience, modulating synaptic and neuronal process in a cell‐type specific manner.ConclusionCellformer opens new perspectives to advance bulk analysis and understand biological mechanisms using cost effective bulk sequencing. Through this study, we showed that cell type‐resolved data nominated potential epigenetic and transcriptional mediators underlying RAD that may illuminate therapeutic opportunities to limit the cognitive impact of this highly prevalent yet stubbornly incurable disease. Cellformer will be made publicly available to advance analysis of high‐throughput bulk ATAC‐seq in future investigations.
Study on the effectiveness of acetylcholinesterase inhibitors in the treatment of primary progressive logopenic aphasia
Authors: Carrier‐Auclair Julie , Laforce Robert , Lavoie Monica 
Published: December 2023

AbstractBackgroundFor over 25 years, cholinesterase inhibitors (ChEIs) have been the main symptomatic treatment for Alzheimer’s disease (AD). Several meta‐analyses have supported their effectiveness in various neurocognitive aspects of amnestic AD. Over 86% of cases of the logopenic variant of primary progressive aphasia (lvPPA) are caused by a similar pathologic process than AD, yet no study has examined the efficacy of ChEIs in this AD variant. We aimed to explore the efficacy of ChEIs in the treatment of lvPPA by comparing their longitudinal MMSEs to that of treated amnestic AD patients.MethodA retrospective chart review was performed on 48 patients with lvPPA and 52 patients with amnestic AD. Both groups were similar with respect to age, level of education, and onset of symptoms. Drug history and MMSE scores were collected on several time points before and after the introduction of ChEIs.ResultsPatients with lvPPA showed a similar trajectory of decline than amnestic AD patients on serial MMSEs (both WORLD and 100‐7) up to twelve months after the introduction of ChEIs (Figure 1 and 2).ConclusionThis study provides preliminary evidence for efficacy of ChEIs in patients with lvPPA and suggests similar benefits to those seen in amnestic AD patients.
Impact of the COVID‐19 Pandemic on Patients with Dementia or Parkinson’s Disease and their Caregivers in Lima, Peru
Authors: Diaz Monica M , Beauchamp Morgan T , Aguilar Ximena R , Bailey Maisie , Coronel Danilo A Sanchez 
Published: December 2023

AbstractBackgroundProgressive neurodegenerative diseases, such as dementia and Parkinson’s disease (PD), lead to difficulties completing activities of daily living (ADLs). In Peru, a low‐to‐middle income country, caregivers are family members who learn to provide caregiving based on the patient’s primary neurologists’ recommendations and through social media. During the COVID‐19 pandemic, Peru had one of the strictest enforced lockdowns, yet the country had one of the highest mortality rates worldwide. Little is known of the pandemic’s effect on patients with neurodegenerative conditions and their caregivers in Peru. This study aimed to examine the effect of the pandemic on patients and caregivers.MethodWe enrolled participants who were caregivers of patients with dementia or PD who receive care at a large public neurology hospital in Lima, Peru. A modified version of the Zarit Caregiver burden scale and a questionnaire on COVID‐19 symptoms, mental and physical well‐being was administered to each caregiver by phone. We performed descriptive statistics.ResultWe enrolled 44 caregivers with females comprising 80% of patients and 60% of caregivers, mean+/‐ standard deviation (SD) age of 73.2+/‐11.4 and 48.6+/‐12.1 years, respectively. More than 70% of patients had dementia and 20.5% had PD. Nearly one‐third of patients tested positive for COVID‐19 and nearly all patients were fully vaccinated with a booster. Nearly all patients (98%) adopted social isolation measures and 86% of patients maintained social connections with family by phone. Unfortunately, many patients had difficulties obtaining medications (48%), felt lonelier (52%), and had an increase in anxiety (60%), agitation (43%), hallucinations (50%), and forgetfulness (71%) compared to before the pandemic.The majority of caregivers had only completed secondary school (34%) with nearly 40% reporting working full‐time in addition to caregiving. We found that 82% felt more overwhelmed with caregiving, 16% reported interruptions in additional caregiving support and 73% needed to dedicate more time to caregiving.ConclusionMore studies are needed to highlight where the most difficult aspects of caregiving in low‐and‐ middle income countries to target caregiving resources and ameliorate caregiving burden worsened during the pandemic. Developing caregiver training sessions to improve patient quality of life is crucial.
A cross‐sectional study of telemedicine use during the COVID‐19 pandemic in people with Alzheimer’s disease
Authors: Patel Anisha M , Schuldt Robert , Boudreau Denise M , Win Nikki , Cobb Bryan R , McGinley Marisa 
Published: December 2023

AbstractBackgroundPeople with Alzheimer’s disease (pwAD) may struggle to access medical care due to declining cognitive function. Telemedicine (TM) provides timely, remote access to AD‐related health services. During the COVID‐19 pandemic, the use of TM increased; however, it is unclear how its use and accessibility vary among commercially insured pwAD.MethodThis cross‐sectional study used US PharMetrics Plus commercial claims data (01/01/2019−12/31/2021). TM use, identified using ≥1 current procedural terminology code, was assessed in each pandemic year (2020 and 2021) in adults with ≥1 inpatient or ≥2 outpatient ICD‐10‐CM diagnosis codes for AD ≥30 days apart. Any TM use and AD‐related visits (AD diagnosis code in TM claim) were summarized, and characteristics of TM users vs nonusers among pwAD were described.ResultAmong pwAD, 48.3% (8948/18,513) in 2020 and 35.7% (7436/20,823) in 2021 used TM. Of these TM users, the mean (SD) number of TM claims was 2.8 (2.6) in 2020 and 2.7 (2.7) in 2021; approximately half had AD‐related TM visits (56.2% in 2020; 48.4% in 2021). Among pwAD, TM visits accounted for 3.0% of all healthcare claims in 2020 and 2.0% in 2021, and approximately a third of these claims were AD‐related (35.5% in 2020 and 32.9% in 2021). Most TM visits among pwAD included ≥1 interactive audio/video component (75.5% in 2020 and 77.8% in 2021) and involved an established patient visit (73.7% in 2020 and 75.3% in 2021). Of 44,303 total TM visits by pwAD in 2020 and 2021, 14.2% were provided by a neurologist. Compared with nonusers, TM users had a higher mean (SD) Charlson Comorbidity Index score (3 [2] vs 4 [2]), were less likely to be self‐insured (22.5% vs 18.1%) and were more likely to reside in western (18.5% vs 28.3%) or eastern (12.7% vs 17.1%) regions. TM use was highest in Massachusetts (83.2%) and California (78.9%).ConclusionOver a third of pwAD in a commercially insured population used TM during the pandemic; its use varied most notably by region and state and among those with a high comorbidity burden. Additional analyses will further inform TM access and its utility in pwAD.
Automatic classification of underlying AD vs. FTLD pathology in people with clinical Frontotemporal Dementia using digital speech markers
Authors: Cho Sunghye , Shellikeri Sanjana , Cousins Katheryn A Q , Ash Sharon , Agmon Galit , Gonzalez‐Recober Carmen , Irwin David J. , Liberman Mark Y , Grossman Murray , Nevler Naomi 
Published: December 2023

AbstractBackgroundRecent studies show promising results using speech features to automatically distinguish patients with amnestic Alzheimer’s disease (AD) from healthy controls (HC). However these studies exclude atypical presentations of AD, which present with linguistic and/or behavioral impairments that clinically overlap with frontotemporal dementia (FTD). A clinically meaningful challenge is distinguishing underlying AD pathology from frontotemporal lobar degeneration (FTLD) pathology in people presenting with an FTD phenotype. We used digital speech features to automatically classify patients with clinical FTD with as to underlying AD or FTLD pathology.MethodWe extracted 90 lexical and 9 acoustic features from one‐minute picture descriptions produced by 179 participants using our previously validated automated pipelines (Table 1). All patients presented clinically with FTD and had AD or FTLD pathology based on either autopsy or CSF (AD: CSF pTau/Aβ42³0.1 and tTau/Aβ42³0.34). Extracted features included part‐of‐speech, unique words per 100 words, several lexical characteristics, and acoustic/durational measures. Support Vector Machine (SVM), Random Forest (RF), and Multilayer Perceptron (MLP) classifiers were trained for two tasks: 1) AD vs. FTLD pathology and 2) all patients vs. HC. Five feature sets were tested: Set 1 (baseline): demographics+MMSE, Set 2: speech only, Set 3: speech+demographics, Set 4: speech+MMSE, Set 5: speech+demographics+MMSE. Features were selected using the elastic net regression with 10‐fold validations; the best performance models were reported after hyperparameter tuning.ResultDistinguishing AD from FTLD, the MLP model trained with speech had the highest AUC (0.88; accuracy = 83%) (Table 2). The RF model trained with speech and MMSE showed similar performance (accuracy = 84%, AUC = 0.85). Verb counts had the highest feature importance (FI) values in the MLP model trained with speech, followed by noun length. Distinguishing all patients from HC, the MLP model trained with speech only had the highest accuracy (93%; AUC = 0.93) (Table 3). The MLP model trained with speech and MMSE showed a comparable result (accuracy = 92%, AUC = 0.94). Unique adjective counts had the highest FI in the MLP model trained with speech, followed by word length.ConclusionSpeech models outperformed baseline models and showed comparable results with speech+MMSE. Features extracted from brief speech samples are valuable in automatically distinguishing AD from FTLD pathology, and FTD from HC.
DDR1 regulates CNS collagen IV expression and vascular fibrosis in AD to improve CNS vascular integrity
Authors: Stevenson Max E , Varghese Rency , Hebron Michaeline , Liu Xiaoguang , Turner R. Scott , Moussa Charbel E‐H 
Published: December 2023

AbstractBackgroundBlood‐brain barrier breakdown, a feature associated with AD pathology and treatments, was examined as a potential therapeutic target in both genetic mouse models of AD and clinical trial data from human patients with AD treated with nilotinib.MethodsDDR1 knockout mice crossed with TgAPP mice were probed for levels of CNS collagen to examine the effects of DDR1 in vivo. CSF samples obtained from AD subjects treated with either nilotinib (n = 12) or placebo (n = 11) for 12 months were analyzed using whole genome RNA sequencing; significantly altered miRNA expression was examined for potential downstream effects regulating neurovascular integrity.ResultsCompared to TgAPP mice, staining of CNS sections for collagen IV in TgAPP/DDR1 knockout mice revealed decreased vascular collagen. CSF obtained from AD subjects treated with nilotinib revealed increased levels of miRNAs regulating collagen production, suggesting decreased vascular fibrosis and neuroinflammation, and improved neurovascular integrity.ConclusionDDR1 inhibition with nilotinib may improve neurovascular integrity in AD by reducing CNS collagen IV, vascular fibrosis, and neuroinflammation. Nilotinib should be considered as an adjunctive therapy to approved treatments ‐ including anti‐amyloid antibodies ‐ for individuals with AD.
Age‐specific Barriers and Facilitators to Research Participation Among Underrepresented African Americans
Authors: Nissim Nicole R. , Fudge Michelle R. , Lachner Christian , Lucas John A. , Graff‐Radford Neill R , Day Gregory S. 
Published: December 2023

AbstractBackgroundAfrican Americans experience a high dementia burden yet are critically underrepresented in observational studies and clinical trials in memory and aging. Lack of adequate representation increases the likelihood that research findings may not generalize to African Americans. A deeper understanding of the barriers and facilitators that influence participation by younger and older African American adults is needed to support recruitment and retention in studies focused on early‐ and late‐onset neurodegenerative diseases.MethodAfrican American community leaders collaborated in design of an electronic survey that was distributed via social media focused on local zip codes. Survey respondents rated barriers and facilitators to research participation on a 0–3‐point Likert scale. Responses ≥2 corresponded with barriers/facilitators likely to influence participation decisions. Differences across age groups were evaluated using nonparametric Kruskal‐Wallis tests. Strategies to mitigate barriers and reinforce facilitators were further explored via community‐based focus groups.ResultSurvey data included responses from 240 African Americans (18‐44‐years, n = 76; 45‐64‐years, n = 83; ≥65‐years, n = 81). Requirement to undergo a diagnostic lumbar puncture was a substantial barrier to research participation across all age groups. Attending weekday visits (median = 2.0), including visits ≥2 hours (median 2.0), was a substantial barrier for individuals 18‐44‐years, but not older respondents (p = 0.001). Compensation for meals/transportation was beneficial across all age groups (median = 2.0; p<0.05). The option to attend visits in the local community or on weekends and access to door‐to‐door transportation were substantial facilitators for respondents <65‐years (median = 2.0) vs ≥65‐years (median = 0; p = 0.001). The option to complete some tests at home was a substantial facilitator for younger (18‐44‐years, median = 2.0) but not older respondents (≥65‐years, median = 0; p = 0.001). Focus group results supported survey findings and showed slight variations in priorities across age groups. Older participants (≥65‐years‐old) more frequently cited the longstanding effects of racism as a barrier to research participation compared to younger participants (45‐64‐years‐old; p = 0.008), who more frequently cited concerns regarding testing requirements (p = 0.034).ConclusionPerceived barriers and facilitators to research participation vary with age. Age‐specific strategies are needed to increase engagement, address disparities in recruitment, and promote retention of African American participants in studies of memory and aging across the lifespan.
Functional investigation of the gliovascular niche‐related genes and their relevance to Alzheimer’s disease pathomechanisms in zebrafish
Authors: Bhattarai Prabesh , Cosacak Mehmet I. , Lee Annie J , Yilmaz Elanur , Is Ozkan , Wang Xue , Vardarajan Badri N , Ertekin‐Taner Nilufer , Mayeux Richard , Kizil Caghan 
Published: December 2023

AbstractBackgroundRecent studies increased the number of genes that are associated with the co‐existence of vascular pathologies and Alzheimer’s disease (AD). However, the biological functions and the mechanism of action by which they contribute to the disease pathology are still to be further elucidated. Therefore, animal models that allow streamlined large‐throughput functional screens in a biologically relevant manner are essential. Towards this goal, we generated adult zebrafish models of amyloid toxicity to functionally analyze candidate genes and how they relate to disease perturbations.MethodThrough cerebroventricular injection of human amyloid‐beta42 monomers into the cerebrospinal fluid of the adult zebrafish brain, we inflict acute amyloid toxicity. By performing immunohistological analyses, single cell transcriptomics, gene editing for generating gene variants or full knockouts, transient functional knockdown of candidate genes, pharmacological intervention of selected signalling pathways and comparing the findings to human AD brain transcriptomics datasets, we determined the similarities and differences of the effects of amyloid pathology on the vasculature in zebrafish in relation to the human conditions.ResultsWe found that amyloid pathology in zebrafish brain shows histological and molecular similarities to human brains. Integration of single cell transcriptomics showed remarkable similarities in neurons to amyloid in humans and zebrafish. We identified several molecular mechanisms that underlie this pathology‐induced cellular response and translated to mammalian models including rodent brains. By performing genome‐wide association in AD patients, we identified that the FMNL2 links cerebrovascular disease and AD, by regulating the astroglial and blood vessel interactions and controlling the efficient clearance of toxic proteins from the brain. Our new single cell transcriptomics analyses of the gliovascular niche cells of the zebrafish brain revealed potential cellular interactions and the pathways perturbed in vascular disease and AD.ConclusionWe propose zebrafish as a useful model for functional investigation of vascular pathology and AD‐related genes identified in clinical studies by providing in vivo biological knowledge on disease mechanisms, on which novel drug development strategies can be based.
Cross‐cohort correlation of plasma biomarkers for Alzheimer’s disease with cognitive measures in the Global Alzheimer’s Association Interactive Network
Authors: Xiao Cally , Gershfeld Seth P. , Pappas Ioannis , Toga Arthur W. 
Published: December 2023

AbstractBackgroundRecent advances in assay development for Alzheimer’s disease (AD) biomarkers in the blood have led to increased sensitivity and specificity for detecting proteins such as the 42 amino acid amyloid‐beta (Aβ42), total and phosphorylated tau protein (t‐tau and p‐tau, respectively), and neurofilament light (NfL).MethodUsing data available in the Global Alzheimer’s Association Interactive Network (GAAIN), contributed by several studies such as the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), the Health and Aging Brain Study: Health Disparities (HABS‐HD), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we correlated AD plasma biomarkers with cognitive diagnosis outcomes in a preliminary analysis. A full study with additional data sets and analysis methods, including controlling for confounding variables such as age, sex, years of education, and co‐existing medical conditions, is planned.ResultUsing logistic regression in the GAAIN Interrogator data analysis tool, we preliminarily found that participants with Aβ42 levels in the upper quartile of all measurements were not associated with mild cognitive impairment (MCI) or dementia diagnoses, the upper quartile of t‐tau and p‐tau181 measurements were associated with dementia but not MCI diagnoses, and the upper quartile of NfL measurements were associated with both MCI and dementia diagnoses.ConclusionBlood‐based biomarker assays that detect proteins implicated in Alzheimer’s disease have the potential for early and accurate diagnosis and are less invasive and costly than lumbar punctures for cerebrospinal fluid (CSF) collection and positron emission tomography (PET) imaging. This meta‐analysis contributes to the growing knowledge base of the prognostic utility of blood‐based biomarker assays.