bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrophysiological insights into resilient individuals: Examining calcium permeable AMPA receptor responses and neuropathological correlations in Alzheimer’s Disease
Authors: Gutierrez Berenice A , Moreno Naomi , Keene C Dirk , Limon Agenor 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a common form of dementia characterized by the accumulation of amyloid beta (Aβ) and phosphorylated tau proteins in the brain. While clinical observations are typically used for AD diagnosis, postmortem studies have revealed individuals without dementia symptoms but with high AD pathology, known as resilient individuals. Calcium permeable AMPA receptors (CP‐AMPARs) have been implicated in the calcium dyshomeostasis of AD, but it is unclear whether they are found or behave differently at the electrophysiological level in resilient and control individuals compared to AD patients.MethodWe examined the differences in responses of synaptic CP‐AMPARs from a cohort of postmortem tissue from 30 individuals, including controls (3M, 4F; non‐demented, no neuropathology), age‐matched AD patients (2M, 5F; individuals with AD of the same age as the control group), resilient individuals (2M, 6F; non‐demented with AD neuropathology), and age‐matched AD patients to resilient individuals (2M, 5F; individuals with AD of the same age as the resilient group). We isolated and microtransplanted synaptic membranes from the parietal cortex of each individual into Xenopus laevis oocytes for recordings of AMPARs through two electrode voltage clamp. We induced agonist responses of AMPARs with the use of kainate and glutamate drugs. To differentiate CP‐AMPARs from calcium‐impermeable AMPARs, we used IEM‐1460 drug, which selectively targets GluR2 subunit‐lacking receptors (CP‐AMPARs) over GluA2‐containing receptors (calcium‐impermeable AMPARs). Additionally, we performed immunoblots from the synaptosomal aliquots of each individual to assess the presence of Aβ/Tau oligomers and determine whether there is a correlation between the amount of toxic oligomers and the strength of the CP‐AMPARs responsesResultOur results suggest that resilient individuals tend to have less CP‐AMPARs synaptic responses compared to individuals with AD and even controls, despite the presence of Aβ/Tau oligomers.ConclusionUnderstanding the differences in synaptic receptors among different groups of individuals provides a foundation for future research into the mechanisms that lead to synaptic alterations in AD.
The moderating effects of sex and amyloid status on the associations between early tau burden and memory
Authors: Lui Kitty K. , Wang Xinran , Stiver Jordan , Wang Xin , Sundermann Erin E. , Betthauser Tobey J. , Jonaitis Erin M. , Langhough Rebecca E. , Johnson Sterling C. , Banks Sarah 
Published: January 2025

AbstractBackgroundOlder women accumulate more pathological tau than older men in the early stages of Alzheimer’s disease (AD). However, the cognitive effects of early tau deposition may be obscured in women given their superior performance on verbal memory tests, which are commonly used in diagnosing AD. Visuospatial memory may more accurately reflect early tau burden in older women due to less apparent sex differences. In the Wisconsin Registry for Alzheimer’s Prevention (WRAP), we examined whether sex and Aβ status moderated associations between tau and verbal and visuospatial memory in older adults.MethodCognitively unimpaired and mild cognitively impaired WRAP participants (n = 196; age = 70.8±4.2; 65.8% female) with [18‐F]MK6240 tau positron emission tomography (PET), [11‐C]Pittsburgh Compound B (PiB) Aβ‐PET, apolipoprotein E ε4 (APOE4) status, and memory scores from the Rey Auditory Verbal Learning Test (RAVLT) and Brief Visuospatial Memory Test‐Revised (BVMT‐R) were included (Table 1). Tau standard uptake value ratio (SUVR) in Braak stages I and II, regions of early tau deposition, were calculated. We used linear models to analyze the effect of sex×Aβ status (distribution volume ratio (DVR)>1.19)×tau interactions on memory, controlling for age at memory assessment, time between memory assessment and PET scans, APOE4 status, and years of education.ResultSignificant sex×Aβ status×tau in Braak stage II interactions were observed on BVMT‐R total learning, BVMT‐R delayed recall, and RAVLT delayed recall (ps<.03), showing that, in Aβ+ women, more tau in Braak stage II was associated with worse performance on these memory outcomes (ps<.01), but not in Aβ+ men (ps>.07; Figure 1). Moreover, in Aβ‐ men, more tau in Braak stage II was related to worse BVMT‐R delayed recall (p = .03), but not in Aβ‐ women (p = .97; Figure 1B).ConclusionThese findings indicate that, in the presence of Aβ pathology, there are impacts of early tau accumulation on both visuospatial and verbal memory in older women more than in older men. Longitudinal studies with ethnoculturally diverse samples will be necessary to clarify our understanding of the relationship between tau accumulation and memory decline and to increase the generalizability of the results.
Increasing the power of rare variant association analyses with common variant eQTLs in Alzheimer’s disease
Authors: Yang Yuchen , Bush William S. 
Published: January 2025

AbstractBackgroundMany independent studies have found rare variants associated with AD. Current gene‐based tests for rare‐variants generally consider the impact of low‐frequency coding variants as an independent effect from the common regulatory variants that surround them. In this work, we propose to increase the statistical power of kernel‐based rare‐variant association tests by accounting for the surrounding cis‐regulatory variants’ effects on gene expression. We intend to identify novel AD associations of genes with rare variants on existing haplotype backgrounds.MethodWe incorporate common variant cis‐eQTLs around the gene or SNP‐set of interest as a fixed effect by estimating their impact on gene expression using GTEx association models. The Sequence Kernel Association Test (SKAT) is then used to test for the residual random effect of coding rare‐variants (MAF<1%). SKAT is known to retain statistical power when a small proportion of test variants are causal, and when these effects are in mixed directions. We perform comprehensive simulation studies that demonstrate the biological conditions under which our method can substantially increase power, including a range of effect sizes for gene expression, providing insight into the relationship between eQTLs and rare variants. Power analyses were performed with both exact p‐values computed via the Davies method and derived empirically through permutation tests.We then applied our approach to data from the Alzheimer’s Disease Sequencing Project to evaluate gene‐level associations across 6461 genes with 210,000 missense rare variants. We also extend this approach to other set‐based rare variant association tests such as SKAT‐O and variant‐set mixed model association tests.ResultSimulations show that our method can substantially increase power, while maintaining the type I error in the absence of association. Our proposed method improves the power of SKAT where a low proportion (<10%) of tested variants have small mixed effect sizes (OR<1.0), closely resembling real world variant effects. We confirm previously reported significant associations such as TREM2, and find several novel gene candidates that required this adjustment to be study‐wide significant.ConclusionOur approach is useful for discovering rare variation in genes that contribute to AD risk and heritability. This method can be flexibly incorporated into many existing analyses pipelines.
ALLFTD: Characterization of Frontotemporal Lobar Degeneration (FTLD) Disease Trajectories through Longitudinal Assessment
Authors: Heuer Hilary W. , Forsberg Leah K. , Mester Carly T. , Kolander Tyler , Johnson Noah , Brushaber Danielle , Rosen Howard J. , Boeve Brad F. , Boxer Adam L. ,   ALLFTD Consortium
Published: January 2025

AbstractBackgroundThe ALLFTD (ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration) study is an NIH‐funded effort to prepare for clinical trials in sporadic (s‐FTLD) and familial (f‐FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. To understand disease trajectories in the context of potential preventative or disease‐modifying therapeutic agents, comprehensive evaluation across multiple time‐points is crucial.MethodALLFTD evaluates participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD‐ALS, CBS, PSP), with strong family histories of FTLD, or known FTLD‐associated genetic variants within the family. ALLFTD has expanded to include 28 expert sites in North America conducting clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants, providing detailed data on participant status and disease progression. Participants are asked to return for annual evaluations. The central data management staff assist sites in retention efforts by providing monthly reports of follow‐up visits that are pending, due, or overdue, based on a 15‐month period from previous visit.ResultSince enrollment began in January 2020, ALLFTD has conducted 1363 baseline visits, including 339 participants previously enrolled in ALLFTD’s predecessor studies (ARTFL and LEFFTDS). Excluding individuals not anticipated to return due to disease progression (123), participant death (55), or recent enrollment (<15 months; 318), ALLFTD has a retention rate of 83% for a second visit despite early enrollment occurring during COVID restrictions. Retention rates for third and fourth visits are even higher (90% and 97% respectively), suggesting a high degree of engagement in longitudinal participants. Including historic data from ARTFL and LEFFTDS, >1000 participants have multiple visits.ConclusionLongitudinal assessment of clinical and biomarker profiles in f‐FTLD and s‐FTLD can inform models of disease onset and progression, allowing analysis of disease trajectories and identification of the most sensitive clinical outcome measures over time. ALLFTD has been successful at recruiting and retaining a large active cohort to obtain detailed clinical and biomarker characterizations; data are available by request.
Neuropsychiatric symptoms and depression across cognitively‐defined AD subgroups at the time of AD diagnosis: data from the National Alzheimer’s Coordinating Center (NACC)
Authors: Choi Seo‐Eun , Scollard Phoebe , Mukherjee Shubhabrata , Gibbons Laura E. , Lee Michael L. , Klinedinst Brandon S , Gallée Jeanne , Sugimoto Taiki , Nakano Connie , Kukull Walter A. , Biber Sarah A , Trittschuh Emily H. , Mez Jesse , Saykin Andrew J. , Crane Paul K. 
Published: January 2025

AbstractBackgroundNeuropsychiatric symptoms are uncommon at Alzheimer’s Disease (AD) dementia diagnosis but are exhibited by nearly everyone during the course of dementia. Depressive symptoms are common in AD dementia. We sought to determine correlations between memory, executive functioning, language, neuropsychiatric symptoms, and depressive symptoms at AD dementia diagnosis, and to characterize neuropsychiatric and depressive symptoms across groups defined by substantial relative cognitive impairments, using data from the National Alzheimer’s Coordinating Center (NACC).MethodUsing confirmatory factor analysis, we derived composite Neuropsychiatric Inventory Questionnaire (NPI‐Q) and Geriatric Depression Scale (excluding the memory question) scores. We defined a reference category of people with AD dementia whose memory, executive functioning, and language scores were similar to each other. Other groups were defined based on relative differences in cognitive domain scores. We used multinomial logistic regression to test if neuropsychiatric and depressive symptoms differed across groups.ResultOur sample included the diagnosis visit for 7,747 people with AD dementia and CDR = 1 (Table 1). Correlations between cognitive domains ranged from +0.29 to +0.50. Correlations between cognitive domains and NPI‐Q composite scores ranged from ‐0.02 to +0.04 and with depressive symptoms from ‐0.09 to +0.14. The correlation between depressive symptoms and the NPI‐Q composite was +0.17. We did not find a difference in NPI‐Q composite scores across groups, but depressive symptom score differed across groups (p<0.0001), with higher scores in people with relatively greater executive functioning impairments and lower scores in people with relatively greater memory impairments, compared to people with similar domain scores (Figure 1, Table 2).ConclusionComposite scores for depressive and neuropsychiatric symptoms facilitate well‐powered investigations of relationships with these clinically salient factors. Neuropsychiatric symptoms had trivial correlations with cognitive domain scores at AD dementia diagnosis, and did not differ across groups defined by substantial relative cognitive impairments. Depressive symptoms were weakly correlated with cognitive domain scores, and differed across groups defined by substantial relative cognitive impairments. More research is warranted to further characterize depression and neuropsychiatric symptoms over the course of AD dementia.
Genetic subtypes of Alzheimer’s disease are related to differential biomarker and cognitive trajectories
Authors: Elman Jeremy A. , Schork Nicholas J. , Rangan Aaditya V 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. We previously identified a genetic heterogeneity across two levels. The first level, which was disease‐relevant but not disease‐specific, comprised three clusters (termed “constellations”) driven by different correlation patterns in a region of extended LD surrounding the MAPT locus. The second level reflected disease‐specific genetic subtypes of AD. These structures were previously found to replicate in an independent dataset. Here, we investigate whether genetic subtypes demonstrate different patterns of biomarker and cognitive trajectories.MethodIn a discovery dataset from the UK Biobank (AD cases = 2,739, controls = 5,478), we applied principal component analysis (PCA) to AD‐associated variants, allowing us to identify three constellations. Subsequently, a biclustering algorithm identified two distinct disease‐specific genetic signatures among subsets of cases not found in controls. We classified individuals with mild cognitive impairment (MCI; n = 399) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) into constellations and determined whether they were a member of either bicluster (i.e., genetic subtype) or not. Longitudinal change in cognitive performance (Preclinical Alzheimer’s Cognitive Composite; PACC), amyloid (florbetapir PET) and p‐tau (CSF) was compared between the two bicluster groups and with non‐bicluster cases.ResultThe disease‐relevant constellations and disease‐specific bicluster structure was apparent in the ADNI MCI sample. Individuals with genetic signatures resembling bicluster 2 exhibited greater decline on the PACC compared to the non‐bicluster (p = 0.022) and bicluster 1 groups (p = 0.004). Bicluster 1 demonstrated a somewhat greater increase in florbetapir over time compared to the non‐bicluster group, but this difference was not significant (p = 0.129). Bicluster 2 demonstrated a significantly greater increase of CSF p‐tau over time compared to the non‐bicluster group (p = 0.041)ConclusionThese results provide additional evidence for the existence of AD genetic subtypes in an independent dataset. The genetic subtypes exhibit differential pathological accumulation and cognitive decline over time, suggesting that this genetic variation has meaningful consequences for downstream processes and disease manifestation.
Genetic architecture of Alzheimer’s disease in a West African Cohort: Insights from the READD ‐ ADSP
Authors: Akinyemi Rufus O. , Griswold Anthony J. , Coker Motunrayo , Whitehead Patrice L. , Rajabli Farid , Akinwande Kazeem S. , Diala Samuel , Ogunronbi Mayowa , Scott Kyle , Obiako Reginald , Adams Larry D. , Hamilton‐Nelson Kara L. , Wahab Kolawole , Mena Pedro R. , Akpalu Albert Kwaku , Kunkle Brian W. , Sarfo Fred Stephen , Vance Jeffery M. , Okubadejo Njideka U , Baiyewu Olusegun , Reitz Christiane , Tosto Giuseppe , Owolabi Mayowa O , Bush William S. , Haines Jonathan L. , Kalaria Raj , Byrd Goldie S. , Ogunniyi Adesola , Pericak‐Vance Margaret A. , Consortium African Dementia 
Published: January 2025

AbstractBackgroundThe “Recruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the ADSP (READD‐ADSP)” is developing a resource to expand ancestral diversity in Alzheimer disease (AD) studies to dissect the genetic architecture of AD across different populations. In addition to US sites, READD‐ADSP includes four US sites and nine countries in sub‐Saharan Africa through the Africa Dementia Consortium (AfDC). The overall goal of READD‐ADSP is to identify genetically driven targets in diverse groups including African Americans and Hispanic/Latinos in US, and Africans. In this preliminary analysis we investigated the ancestral genetic differences and the impact of known AD risk factors within West African cohorts.MethodGenome‐wide genotyping was performed on 91 AD cases and 97 cognitive unimpaired controls from Nigeria and Ghana. APOE alleles and ABCA7 deletion (rs142076058) were sequenced using Sanger. We calculated global ancestry (principal components) using the PC‐AiR approach that is robust to known and cryptic relatedness. We investigated known AD loci from non‐Hispanic White (NHW) and AA genome wide association studies. For association analysis, we employed a mixed‐model regression approach (SAIGE) where we controlled for age, gender, population substructure (first three principal components), and relatedness.ResultPrincipal component analysis identified a distinction between the Ghana and Nigerian cohorts along the first principal component (PC1). Among the genetic loci examined, several showed nominal significance. Notably, the most prominent marker was found in SORL1 (rs17125523; p = 2 × 10‐3). Additionally, we discovered an exonic nonsynonymous marker in the BIN1 gene (rs112318500), which is specific to African ancestry and showed a protective effect. APOE e4 allele showed a significant association with AD risk (OR = 2.5; CI:1.5‐4.2; pv = 0.001), while the e2 indicated a protective trend but did not reach statistical significance. No statistical difference in the frequency of ABCA7 deletion was observed between AD and CU individuals.ConclusionOur findings highlight the presence of genetic variations between West African populations that warrant further investigation, potentially offering new insights into the genetic underpinnings of AD. Data collection is ongoing across the AfDC and updated data will be presented.
Vascular‐based risk scores for the prediction of Alzheimer’s disease pathology biomarkers and cognitive status in older adults at‐risk for dementia: Exploratory analysis of sex and ethno‐racial differences
Authors: Udeh‐Momoh Chinedu , Duran Tugce , Hughes Timothy M. , Sai Kiran K. Solingapuram , Bateman James R. , Byrd Goldie S. , Mielke Michelle M. , Craft Suzanne , Lockhart Samuel N. 
Published: January 2025

AbstractBackgroundVascular‐based dementia risk scores (VDRS) which reliably predict risk of Alzheimer’s disease and related dementias (ADRDs), may be useful to identify at‐risk individuals for secondary prevention trials. Dementia risk scores have typically focused on predicting ADRD‐associated symptoms, with fewer studies assessing capacity for detecting individuals with underlying brain pathologies. We compare the predictive value of two vascular‐based risk scores (CAIDE and Reitz VDRSs) for discriminating AD‐related histopathological and structural abnormalities, further considering race and gender differences.MethodWe included non‐demented (self‐identified) White and Black participants at the Wake Forest ADRC Clinical Core with baseline UDSv3 cognitive testing (used to calculate the Preclinical Alzheimer’s Cognitive Composite ‐ PACC5), clinical adjudication, amyloid (PiB) PET, APOE genotype, and metabolic characterization for diabetes including prediabetes. WHICAP/Reitz scores were calculated using components of sex, education, age, race, ethnicity, hypertension, diabetes, WHR, HDL, smoking and APOE‐ε4 status. CAIDE scores included age, education, sex, systolic BP, BMI, physical activity, total cholesterol, and APOE‐ε4. We assessed differences in VDRS among cognitive, amyloid PET and racial groups.Result616 participants (Table 1) had baseline data available for analysis. Of 287 with amyloid PET, 33% were amyloid positive (CL>20). Median Reitz scores differed by cognitive status (Figure 1A), with higher mean scores noted for those with amnestic (aMCI) and non‐amnestic MCI (naMCI) compared to those with normal cognition (naMCI/aMCI: median 17, p<.001). Reitz scores were also significantly higher in amyloid positive vs negative participants (Figure 1C) as well as in Black vs White participants (Figure 2A) (median (IQR): 16 (2,34) vs 12 (0,28), 17 (0,33) vs 14 (0,40) respectively; p<.001), however no sex differences were noted. In contrast, we found no significant differences in CAIDE scores among cognitive and amyloid pathology groups (p>0.05, Figures 1B and 1D), except ethno‐racial groups (p<.001, Figure 2B).ConclusionSignificant differences in distinct VDRSs were found in relation to brain amyloid pathology levels and clinico‐cognitive status, with ethno‐racial influences potentially contributing to noted differences. Risk composites accounting for these factors will be useful for greater precision around pre‐selection of at‐risk populations towards targeted trials for disease modifying therapies and optimal management of clinical care.