bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association Between Age and Cognitive Severity in Early‐Onset AD: Extension of preliminary findings in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS)
Authors: Hammers Dustin B. , Eloyan Ani , Taurone Alexander , Thangarajah Maryanne , Kirby Kala , Wong Bonnie , Dage Jeffrey L. , Nudelman Kelly N. , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Bradford C. , Apostolova Liana G. ,   LEADS Consortium
Published: January 2025

AbstractBackgroundWidespread cognitive impairments have previously been documented in Early‐Onset Alzheimer’s Disease (EOAD) relative to cognitively normal (CN) same‐aged peers or those with cognitive impairment without amyloid pathology (Early‐Onset non‐Alzheimer’s Disease; EOnonAD; Hammers et al., 2023). Prior preliminary work has similarly observed worse cognitive performance being associated with earlier ages in EOAD participants enrolled in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS; Apostolova et al., 2019). It is unclear, however, if these age effects are seen across early‐onset conditions, and whether cognitive discrepancies among diagnostic groups are uniform across the age spectrum. The objective of the current study is to more‐extensively examine the impact of age‐at‐baseline on cognition within LEADS, with emphasis placed on the influence of diagnostic group on these associations.MethodExpanded cross‐sectional baseline cognitive data from 573 participants (CN, n = 97; EOAD, n = 364; EOnonAD, n = 112) enrolled in the LEADS study (aged 40‐64) were analyzed. Multiple linear regression analyses were conducted to investigate associations between age‐at‐baseline and cognition for each diagnostic group – and their interaction among diagnoses – controlling for gender, education, APOE ε4 status, and disease severity.ResultSee Table 1 for demographic characteristics of our sample. Linear regression showed a significant interaction effect for the cognitive domain of Executive Functioning (p = .002). Specifically, while the EOAD group displayed a positive relationship between age‐at‐baseline and Executive Functioning performance (β = 0.08, p = .02; Figure 1), the CN group displayed a negative relationship (β = ‐0.04, p = .008) and the EOnonAD group displayed no relationship (β = ‐0.01, p = .50). A similar main‐effect for age was observed for the EOAD group when examining Visuospatial Skills (β = 0.12, p = .04), however no other age effects were evident across other diagnostic groups or cognitive domains (Episodic Memory, Language, or Speed/Attention; Table 2).ConclusionBuilding off preliminary work, our results suggest that executive functioning may be disproportionately impacted earlier in the disease course in participants with EOAD relative to other diagnostic groups. This finding appears to be unique to executive functioning, as it was absent in other cognitive domains and remained after accounting for disease severity. This highlights the need for further investigation into executive dysfunction early in the course of EOAD.
Identification of genetic risk factors for brain amyloid deposition
Authors: Patel Maulikkumar P , Fan Kang‐Hsien , Johnson Matthew , Cetin Arda , Ali Muhammad , Western Daniel , Liu Menghan , Gorijala Priyanka , Budde John P. , Cohen Ann D , Lopez Oscar L. , Feingold Eleanor , Pottier Cyril P , Kamboh M. Ilyas , Cruchaga Carlos 
Published: January 2025

AbstractBackgroundAmyloid PET imaging is a promising biomarker to track the accumulation of parenchymal amyloid beta (Aβ) deposits in the brain. Recent large‐scale genome‐wide association studies (GWAS) reported common risk factors associated with amyloidosis, suggesting that this endophenotype is driven by genetic variants. We hypothesized that genes with multiple variants with deleterious effect are associated with Aβ accumulation. To address this issue, we performed whole‐genome sequencing (WGS) on a large cohort of individuals with amyloid PET imaging.MethodIn this study, we carried out a (GWAS) on European‐ancestry individuals with amyloid PET imaging from two cohorts [MAP (Memory & Aging Project), and Pitt (University of Pittsburgh)]. WGS was performed using Illumina Hiseq followed by GATK variant calling as well as extensive variant and ‐individual level quality check. Functional annotation was performed using snpEff and dbNFSP. Only variants predicted loss of function (stop loss/gain, splicing, and frameshift variants), defined as high effect; or with Combined Annotation Dependent Depletion score greater than 25, defined as moderate effect, were included. The amyloid PET harmonized z‐score was used as a quantitative phenotype in our SKAT‐O gene based analyses.ResultAfter quality control, we retained 1,228 participants (52% female). Gene‐based analyses identified a study‐wide significant association for APOE (p‐value = 1.82 × 10‐09), and eight additional genes with suggestive significance association (p‐value<7.5 × 10‐04) including MPDZ, SEC16A, PLBD1, GLB1L2, KCNMB4, ELOVL5, SCART1 and SCN7A. According to the GTEx portal, five of these candidate genes are expressed in the brain. MPDZ encodes for a modular scaffold protein that was recently reported to be associated with Alzheimer’s disease in African‐Americans, supporting its involvement in amyloidosis risk (Ray et al., MedRxiv, 2023)ConclusionWe present the first time, a gene‐based association study assessing the effect of potentially deleterious variants on amyloidosis. Importantly, we show that variants located in the APOE gene have a strong effect on this endophenotype. Interestingly, we point out additional candidate genes such as MPDZ that are potentially associated with amyloidosis. Additional replication, however, is required to validate our findings.
ABCA1 missense mutations are associated with Lewy body dementia
Authors: Ray Anindita , Reho Paolo , Logroscino Giancarlo , Barmada Sami , Ross Owen A. , Scholz Sonja W , Consortium International LBD Genomics 
Published: January 2025

AbstractBackgroundLewy body dementia (LBD) is the second most prevalent dementia in the United States after Alzheimer’s disease (AD). Recent studies have implicated rare mutations in two lipid transport genes, ABCA1 and ATP8B4, in Alzheimer’s disease. Substantial co‐pathology and shared risk factors indicate an intersectional genetic architecture between LBD and AD; therefore, we investigated the association of rare mutations in ABCA1 and ATP8B4 with LBD. Additionally, we examined rare mutations in 25 genes involved in ABCA1‐related lipid‐specific pathway with risk of developing LBD.MethodWe annotated rare missense and loss‐of‐function (LOF) mutations in ABCA1 and ATP8B4 genes, using Ensembl Variant Effect Predictor, in previously published whole‐genome sequence data from 2,591 LBD cases and 4,027 healthy controls of European ancestry. To test the association with LBD risk, we applied the optimized sequence kernel association test (SKAT‐O), followed by single‐variant association test (Fisher’s exact test), and multiple testing (Bonferroni correction). Additionally, we evaluated rare coding variants of 25 genes in ABCA1‐related positive regulation of the cholesterol efflux pathway (GO: 0010875) by performing single‐gene burden and gene‐set burden analyses.ResultsWe found a significant enrichment of rare ABCA1 missense mutations in LBD (SKAT‐O p = 2.68E‐02). However, no significant associations were found between LBD and ABCA1 LOF, and ATP8B4 LOF or missense mutations. Interestingly, the single‐variant analysis identified two ABCA1 missense variants, c.5398A>C; p.N1800H (Fisher’s test: p‐value = 1.16E‐04) and c.3544G>A; p.A1182T (p‐value = 4.29E‐02), with the p.N1800H substitution surviving Bonferroni multiple testing. The p.N1800H variant is reported to be pathogenic, and it was observed in twelve LBD patients and one control, with an odds ratio of 18.48 (95%CI = 2.4‐142.8). This mutation is reported to be pathogenic, in our LBD cohort, six out of twelve ABCA1 p.N1800H carriers also carry the APOE ε4 risk allele. However, neither a single‐gene burden nor a gene‐set burden analysis in 25 genes in the positive regulation of the cholesterol efflux pathway revealed any significant associations with LBD.ConclusionOur findings reveal significant enrichment of ABCA1 missense mutations in LBD emphasizing the genomic complexity surrounding LBD and AD.
Whole blood DNA methylation profiles of Alzheimer’s disease differ across ancestrally diverse populations
Authors: Gu Tianjie , Gomez Lissette , Mews Makaela , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Sanchez Jose Javier , Adams Larry D. , Mena Pedro R. , Starks Takiyah D. , Silva‐Vergara Concepcion , Illanes‐Manrique Maryenela Z. , Cuccaro Michael L. , Vance Jeffery M. , Cornejo‐Olivas Mario , Byrd Goldie S. , Feliciano‐Astacio Briseida E. , Haines Jonathan L. , Beecham Gary , Pericak‐Vance Margaret A , Bush William S. , Griswold Anthony J. 
Published: January 2025

AbstractBackgroundPrior studies have shown differences in the genetic etiology and clinical presentation of Alzheimer’s Disease across populations. For example, for multiple genetic loci associated with AD, effect sizes can vary drastically between individuals of different ancestral backgrounds. Few investigations into differences in epigenetic features like DNA methylation have been conducted in AD, particularly in diverse individuals. These studies are critical to identify and further characterize mechanisms of disease allowing for development of therapeutic interventions.MethodAs part of an ongoing study of the genetics and epigenetics of AD in diverse populations, we performed a methylome analysis of 626 individuals. DNA from whole blood was analyzed using the Illumina MethylationEPICv2.0. The cohort consisted of both AD and cognitively unimpaired (CU) individuals of European (68 AD, 67 CU), African (98 AD, 106 CU), or Hispanic (Puerto Rican (85 AD, 76 CU); Peruvian (41 AD, 41 CU); Cuban (22 AD, 22 CU)) backgrounds. We analyzed data using the SeSAMe R package for quality control and statistical analysis. We performed differential methylation analysis between AD and CU in the overall dataset and within each ancestral population using linear models with covariates sex, age of exam, batch effect, global ancestry and estimated immune cell type proportions.Result878,853 CpG sites were tested for differences between AD status. In a preliminary analysis of these data, we identified 563 CpG sites with nominally significant differences (p‐value ≤ 0.001) between AD and CU. Within each ancestral group, the number of differentially methylated sites differed: European – 442 sites, African – 217 sites, Hispanic – 475. Notably, however, the markers within the ancestral group did not overlap, implying that the AD disease process may be quite different across populations.ConclusionWhile these results are preliminary, and expansion of the dataset may reveal convergence of methylation patterns across ancestral populations, our analyses suggest the possibility of ancestry specific whole blood DNA methylation patterns as signatures of AD pathogenesis. Ultimately, combining these methylation profiles with existing genomic and transcriptomic data may reveal distinct genes but similar underlying pathological processes contributing to AD across individuals of diverse ancestries.
Accuracy of Figure Memory Test of the Brief Cognitive Screening Battery to predict amyloid status in older adults with Subjective Cognitive Decline
Authors: Neto Adalberto Studart , Coutinho Artur Martins , Carneiro Camila de Godoi , Moraes Natália Cristina , Spera Raphael Ribeiro , Yassuda Monica Sanches , Brucki Sonia Maria Dozzi , Buchpiguel Carlos Alberto , Nitrini Ricardo 
Published: January 2025

AbstractBackgroundSome older adults with subjective decline (SCD) had a positive amyloid biomarker indicating a preclinical stage of Alzheimer’s disease.ObjectivesTo assess the accuracy of Delayed Recall of Figure Memory Test (DR‐FMT) of Brief Cognitive Screening Battery to predict amyloid status in SCD older adults.MethodThe sample consisted of 45 older adults classified as SCD and 25 as cognitively unimpaired (mean age of 76.4 and 73.5, respectively, p = 0.138). They were evaluated with BCSB and a standard neuropsychological battery (which includes MMSE, MoCA, RAVLT, Logical Memory and DR of Rey Complex Figure). Subjects were underwent PIB‐PET to assess their amyloid status and images were classified based on visual and semi‐quantitative analyses with 3D‐SSP methodology.ResultTwelve SCD older adults (27.3%) were positive amyloid against six in the controls (23.1%). In SCD group, DR‐FMT was the only memory test that correlated with SUV in amyloid PET (r = ‐0.514, p < 0.001). Only DR‐FMTshowed significant area under the curve (AUC) in the ROC curve in SCD older adults (AUC = 0.771, 95% CI 0.621 ‐ 0.921). Among SCD older adults, DR‐FMT < 8.0 had a sensitivity of 83.3%, a specificity of 68.7% and an accuracy of 72.7%.ConclusionFMT proved to have a good sensitivity and accuracy to predict amyloid status in SCD older adults.
Visual memory is primarily impacted by tau load in the right hemisphere
Authors: Arias Jaime Fernandez , Therriault Joseph , Servaes Stijn , Macedo Arthur C. , Wang Yi‐Ting , Rahmouni Nesrine , Socualaya Kely Monica Quispialaya , Aumont Etienne , Trudel Lydia , Hosseini Seyyed Ali , Hall Brandon J , Chan Tevy , Kunach Peter , Mathotaarachchi Sulantha , Vitali Paolo , Rosa‐Neto Pedro 
Published: January 2025

AbstractBackgroundClassical literature has pointed at lateralization of the relationship between memory scores and cerebral hemisphere injury. Epilepsy studies have suggested an association between left hippocampal damage and verbal memory deficits, and between right hippocampal damage and visual memory deficits. We aimed to explore this concept in the context of tauopathy due to Alzheimer’s disease.Methodwe assessed 132 cognitively unimpaired (CU) older adults, and 44 cognitively impaired (CI), amyloid‐β positive individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. All participants had amyloid‐PET with [18F]AZD4694 and tau‐PET with [18F]MK6240, verbal memory assessments with Rey Auditory Verbal Learning Test (RAVLT), and visual memory assessments with Aggie Figures Learning Test (AFLT). We conducted voxel‐wise analyses to explore the relationship between tau PET and memory modality. In addition, we run regression models with right or left tau temporal metaROI as predictor and memory scores as outcome variables. We entered global amyloid (PET), sex, age, years of education, ApoE status, grey matter volume and handedness as covariates. Finally, we used the laterality index (LI) to investigate correlations with memory modality. Right laterality is indicated by an LI below 0, while left laterality would be signaled by an LI above 0.Resultvoxel‐wise analyses suggested a lateralized relationship between tau and visual memory scores on the right hemisphere, whereas tau and verbal memory scores were bilaterally associated. Regression analyses showed a trend towards a stronger relationship between temporal tau on the right and visual memory scores. The LI was significantly associated with visual memory performance. Further analyses showed that this relationship seems to be driven by tau positive individuals.Conclusionvisual memory performance might be more prominently affected by tau load on the right hemisphere in Alzheimer’s disease. Furthermore, a hemispheric imbalance in the amount of tau is related to visual, but not verbal, memory scores.
Exploring the relationship between neuropsychiatric symptoms, cognitive test performance, and brain abnormalities in a cohort of older adults in rural South Africa
Authors: Gao Sarah , Bassil Darina T. , Farrell Meagan T. , Wagner Ryan G. , Manly Jennifer J. , Brickman Adam M. , Tollman Stephen , Berkman Lisa F. 
Published: January 2025

AbstractBackgroundPeople with Alzheimer’s Disease (AD) often have neuropsychiatric symptoms. The Neuropsychiatric Inventory (NPI) is a validated tool for assessing the severity of these symptoms, but its applicability in a South African context remains unexamined. This study evaluated NPI‐Q, a brief version of the NPI, in relation to cognitive performance and markers of brain atrophy and emotional regulation among older South African adults.MethodData were from Cognition and Dementia in the Health and Aging in Africa: A Longitudinal Study in South Africa (HAALSI‐HCAP), a population‐based nested cohort study in Agincourt, South Africa. The survey included a cognitive battery, clinical examination, and informant interview to assess perceived cognitive and functional changes in respondents. During the informant interview, the NPI‐Q was completed, and a severity score was derived from the cumulative sum of reported individual symptom scores (range: 0‐36). The final sample included 626 participants (71.9±11.3 years‐old, 35.6% men, 56.6% without formal education), of whom 185 underwent MRI scans. Pairwise correlations assessed the relationship between informant reported symptom severity with cognitive measures and MRI‐generated bilateral amygdala volume.ResultA total of 95 informants (15.2%) reported any neuropsychiatric symptoms, averaging 2.48 per participant among those who reported any symptom. Hallucinations were the most common symptom (5.4%), while disinhibition was the least (1%). Among those who reported symptoms, average symptom severity score was 4.28 (SD: 3.65). Severity was significantly correlated (p‐value<0.001) with most cognitive measures assessing general cognition (β: ‐0.27, ‐0.17), episodic memory (β: ‐0.26, ‐0.17), language (β: ‐0.28, ‐0.12), and executive function (β: ‐0.26, ‐0.12). However, no relationship was observed between neuropsychiatric symptoms and visuospatial functioning or amygdala volume, possibly attributable to high rate of missingness for visuospatial measures (30%), and the small MRI sample size reporting symptoms (n = 26).ConclusionNPI‐Q symptoms were associated with lower cognitive performance, revealing a significant relationship between symptom severity and cognitive performance across all measures of the HAALSI‐HCAP cognitive battery, except for those evaluating visuospatial function. Associations between neuropsychiatric symptoms and bilateral amygdala volume were less evident. These results contribute to understanding the impact of neuropsychiatric symptoms on cognitive health in aging South African populations.
Accuracy of cognitive and functional screening tests to Clinical Dementia Rating in an Outpatient Memory Clinic
Authors: Moro Giovanna Correia Pereira , de Souza Aline Siqueira , da Silva Viana João Vitor , Engelmann Gabriela Tomé Oliveira , Burgos Ivonne Carolina Bolaños , Dias Bruna Fugêncio , Moreira Carolina Mizerani Couto , Kosac Karoline Freire , de Oliveira Hansen Erika , Romano‐Silva Marco Aurélio , Viana Bernardo de Mattos , Bicalho Maria Aparecida Camargos 
Published: January 2025

AbstractBackgroundShort screening tools designed to detect cognitive impairment are important for clinical and research. The Clinical Dementia Rating (CDR) is the main used categorization system, which classifies from no dementia, to questionable dementia/mild cognitive impairment (MCI) and three severities of dementia.ObjectiveTo conduct an accuracy analysis of different short screening tests to predict CDR scores on a cohort of a Memory Clinic.MethodsThis is a cross‐sectional study, using data from the Cog‐Aging cohort study in 2023. Participants go through a comprehensive clinical, neuropsychological and neuroimaging assessment to determine the diagnosis and CDR. Eighty participants were recruited: 11 controls, 43 MCI, and 26 Dementia. Mini Mental State Examination (MMSE), Figure Memory Test’s delayed recall in the Brief Cognitive Screening Battery (FMT‐BCSB), The Consortium to Establish a Registry for Alzheimer’s Disease’s word list delayed recall (DR‐CERAD) and Short‐version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were used to distinguish the CDR scores. Participants were classified based on CDR (0; 0.5; and 1‐2). We performed a Receiver Operating Characteristic (ROC) curve and cut‐off values defined by Youden’s J statistic comparing: CDR 0 x CDR 0,5; CDR 0,5 x CDR 1‐2; CDR 0 x CDR 1‐2. This study was approved by the ethics committee of UFMG.ResultsParticipants had a mean age of 77.7 yr. (SD 6.9) and median 6.1 years of education (IQR 5.25). The DR‐CERAD had the best area under the curve (AUC) (0.863) to distinguish CDR 0 to 0.5, with 88% sensitivity with cut‐off points of 5 / 6. Comparing CDR 0.5 to 1‐2, IQCODE had the largest AUC (0,884) with 92% sensitivity with cut‐off ≥ 3,78. Comparing CDR 0 to 1‐2, the DR‐CERAD had the largest AUC (0.987), with 88% sensitivity with cut‐off points of 3 / 4.ConclusionThese findings suggest that DR‐CERAD is the most accurate to distinguish MCI to normal cognition, and normal cognition to dementia in this sample. IQCODE presented as the best to distinguish MCI to dementia. These are preliminary results and more studies with years of education and a larger sample are necessary.
A Multi‐Omic Analysis of Molecular Risk and Resilience Factors in Late‐Onset Alzheimer’s Disease in APOEe4 Carriers
Authors: Markov Yaroslav , Priyanka Ahana , Higgins‐Chen Albert 
Published: January 2025

AbstractBackgroundWhile the apolipoprotein E (APOE) ε4 allele is a well‐known risk factor for late‐onset Alzheimer’s disease (LOAD), not all carriers develop the condition, suggesting the presence of resilience and/or risk factors. The molecular signatures of resilience/risk in the brain, however, have not been thoroughly described, partly due to the scarcity of healthy APOEe4 carriers. This study addresses this gap using a novel multi‐tissue, multi‐omic dataset from the Religious Order Study and Memory and Aging Project cohorts highly enriched in APOEe4 carriers with and without LOAD.MethodOur dataset encompasses post‐mortem samples from three brain regions – superior temporal gyrus (ST), prefrontal cortex (PFC), and cerebellum (CBM) – which exhibit varied susceptibility to AD pathology. Utilizing Illumina EPIC arrays for DNA methylation profiling, deep whole exome sequencing, and label‐free mass spectrometry for protein quantification, we analyze samples from 23 APOE 2/4, 197 APOE 3/4, 17 APOE 4/4, and 96 APOE 3/3 carriers (age range 65 to 108, median 89). This diverse cohort includes 78 individuals without cognitive symptoms, 81 with mild cognitive impairment, and 174 with clinically diagnosed AD dementia, further stratified by NIA Reagan scores, allowing us to rigorously define AD diagnosis based on both clinical and post‐mortem assessments.ResultWe delineate molecular changes associated with resilience/risk to AD specifically in APOEe4 carriers within each brain region. For example, we find sets of 76, 43, and 74 mutated genes strongly associated with AD resilience/risk in ST, PFC, and CBM respectively, featuring an enrichment in genes important for the extracellular matrix. Mutations in these genes, alongside with alterations in DNA methylation and protein levels, may potentially reflect an array of influences, including genetic, environmental, and aging effects, and could provide crucial insights into intervention strategies. For the next phase of this project we will integrate these molecular signatures identified at individual ‐omic levels using a multimodal machine learning approach to further investigate their relevance and interplay in the context of AD resilience/risk.ConclusionThis comprehensive study illuminates the molecular landscape of Alzheimer’s disease resilience and risk factors in APOEε4 carriers, setting the stage for future integrative, multi‐omic analyses.