bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene‐based polygenic score analysis identifies novel immune genes with deleterious variants that associate with Alzheimer’s disease
Authors: Reddy Joseph S. , Wang Xue , Allen Mariet , Carrasquillo Minerva M. , Biernacka Joanna M , Gregory Jenkins D. , Coombes Brandon J , Ertekin‐Taner Nilufer , Younkin Steven G. 
Published: December 2022

AbstractBackgroundIn the Alzheimer’s disease sequencing project (ADSP) whole exome dataset, only the well‐known TREM2.pR47H variant shows genome‐wide significance by conventional single variant analysis. To identify novel AD genes related to TREM2, we used gene‐based polygenic score analysis (PGSA) to evaluate an immune, temporal cortical co‐expression network with 229 genes including TREM2.MethodThe most recent whole exome variant call files from the ADSP (NG00067.v7) were subjected to stringent quality control. Post‐QC samples were divided into discovery (4174 samples sequenced at Broad), test (3299 samples sequenced at WashU), and follow‐up (2273 samples sequenced at Baylor) sets. The pruned variants (r2 < 0.2) with a minor allele count over 20 in each gene were analyzed by Broad/WashU PGSA thereby obtaining P‐values (gPbr.wa) for each gene in WashU samples. To assess significance in independent Baylor samples, cumulative Broad/Baylor PGSA was performed using a novel approach in which variants were stratified by both gene (gPbr.wa) and variant (Broad.P).ResultAfter excluding TREM2, the five variants with gPbr.wa ≤ 0.08 and Broad.P ≤ 0.03 showed significant association in Broad/Baylor PGSA. One of these variants showed no evidence of association with AD in the combined dataset. Polygenic scores for the other four variants, which were in three genes, showed significant association in Baylor samples, and significant, essentially identical association in WashU samples. Polygenic scores for nine additional variants in these genes (0.03> Broad.P ≤ 0.13) also showed significant, essentially identical association in Baylor and WashU samples. The association of these 13 variants with AD was driven primarily by six deleterious, protein‐altering variants with minor allele frequencies less than 1%, but the other 7 variants also contributed.ConclusionUsing gene‐based polygenic score analysis to analyze an immune co‐expression network, we identify three novel immune genes with actionable nonsynonymous and stopgain variants that show significant, replicable association with AD in the most recent release of the ADSP whole exome dataset.
Exploring Care Service Use Among Latino LGBTQ+ Caregivers of Persons Living with Alzheimer’s Disease and Related Dementias
Authors: Kittle Krystal R. , Flatt Jason D. , Perales Jaime , Anderson Joel G 
Published: December 2022

AbstractBackgroundLatino and lesbian, gay, bisexual, transgender or queer (LGBTQ+) adults are both growing populations at increased risk of Alzheimer’s disease and related dementias (ADRD). The increased prevalence in ADRD among these populations requires caregiving that is often met by informal caregivers. Yet, very little is known about the experiences of informal ADRD caregivers who identify as both Latino and LGBTQ+.MethodWe examined differences in sociodemographic characteristics, caregiving characteristics, and use of caregiver support services between English‐proficient Latino and non‐Latino LGBTQ+ ADRD caregivers recruited via social media (n = 286; Latino n = 103).ResultLatino caregivers identified as gay (45%), lesbian (24%), bisexual (20%), and queer/other (11%). Sixty‐one percent identified as cisgender (not transgender) women, 39% cisgender men, and 19% identified as transgender. On average, Latino caregivers were younger (36 vs. 38 years old), reported a lower percentage of individuals who completed a college degree (36% vs. 51%), a higher income (64% vs. 50%), and a lower percentage of being married or partnered (44% vs 63%). Latino caregivers were in their caregiving roles for seven months less than non‐Latino caregivers, and reported a greater (8% vs. 6%) presence and severity of behavioral symptoms of distress (e.g., agitation, disrupted sleep) among their care recipients living with ADRD. Latino caregivers indicated their care recipients had less dependence in activities of daily living (1.3 vs. 1.8) and more independence in instrumental activities of daily living (5.1 vs. 4.2). Latino caregivers also reported lower use of respite services (38% vs. 51%), transportation services (37% vs. 53%), and making home modifications (34% vs. 71%) for their care recipients living with ADRD.ConclusionFindings indicate Latino and non‐Latino LGBTQ+ ADRD informal caregivers differed in sociodemographic characteristics, length of time caregiving, and the presence and severity of behaviors and functioning levels of their care recipients living with ADRD. Latino caregivers utilized caregiver support services to a lesser degree than non‐Latino caregivers. More research is needed to understand ways to address the needs and better serve this growing population.
Exploring Cognitive Impairment in a Community‐Based Sample of LGBTQ+ Older Adults
Authors: Flatt Jason D. , Evans Alexandria , John Samantha E , Correro Anthony N , Kittle Krystal R. , Cicero Ethan C. , Wharton Whitney , Anderson Joel G 
Published: December 2022

AbstractBackgroundOver three million adults aged 60+ in the U.S. identify as lesbian, gay, bisexual, transgender, queer, or another sexual and/or gender minority identity (LGBTQ+). Population‐based studies have found a higher prevalence of subjective cognitive decline among LGBTQ+ adults compared to non‐LGBTQ+ adults. Less is known about objective cognitive impairment in LGBTQ+ older adults.MethodWe recruited a community‐based sample of LGBTQ+ older adults (n = 61) from low‐income housing registries. The Telephone Interview for Cognitive Status (TICS; Brandt et al., 1988), an 11‐item screening test of global cognition. Descriptive statistics were used to summarize demographic characteristics, TICS scores, and the prevalence of cognitive impairment. We also examined associations between TICS score (adjusted for age and education) and self‐reported physical and mental health limitations.ResultMean age was 70.8 (SD = 5.8, range = 58‐84). Most reported their sex assigned at birth as male (67%), and 5% identified their gender as transgender or non‐binary. Most participants identified as lesbian or gay (85%), with 7% identifying as bisexual, and 8% queer or another sexual orientation. The majority (90%) identified as White, 7% Black, and 3% Latino. Over 62% of participants had a four‐year college degree or higher. Nearly 80% reported an annual income ≤$30,000. Common chronic health conditions included depression (57%), anxiety (48%), hypertension (46%), post‐traumatic stress disorder (26%), and human immunodeficiency virus infection (21%). About 40% (n = 24) reported problems with their memory. TICS median score was 33.0 (SD = 3.55, range = 21‐39). Nearly 43% (n = 26) may have cognitive impairment (i.e., TICS score of ≤32). A lower TICS score was associated with reporting limitations in daily activities (p = 0.02) and social activities with family and friends (p = 0.04) over the past four weeks.ConclusionOver 40% of LGBTQ+ older adults scored in the impaired range on a screening measure of global cognition. Clinically, more comprehensive evaluations would clarify the extent of decline present among the current sample. Follow‐up studies are needed to better understand the cognitive functioning of LGBTQ+ older adults as some subgroups report more memory problems relative to non‐LGBTQ+ groups. Moreover, inclusive recruitment and outreach efforts are essential so the voices of all LGBTQ+ subgroups can be accurately portrayed in clinical research.
Cognition research in LGBTQIA+ groups: What’s it mean for Alzheimer’s research?
Authors: Stites Shana D. , Bonsu Edna , Harkins Kristin , James Richard 
Published: December 2022

AbstractBackgroundOlder adults who are members of sexual and gender minoritized (SGM) communities, including lesbian, gay, bisexual, transgender, queer, intersex, asexual and other identity (LGBTQIA+) groups, are at high risk of cognitive problems and caregiving deficits. Sexual orientation is a social and structural determinant of health (SSDOH), impacting cognitive health and medical management as members of SGM groups encounter social and structural barriers that could be impacting cognition directly and indirectly, and research is needed to understand pathways that lead to those elevated risks. So, what type of cognition research is being conducted with LGBTQIA+ groups and how does it herald inclusion of these groups in Alzheimer’s studies?MethodsWe conducted a broad search of Pubmed, Embase, and PsychINFO (ProQuest platform) databases for January 2000 to December 2020 using search key terms for constructed related to: LGBTQIA, cognition, and Alzheimer’s disease and related dementias (AD/ADRD). Abstracts were analyzed to identify studies reporting on medical conditions. We report summary statistics to describe the topics, conceptual frameworks, sample characteristics, and methods in those studies with a focus toward the relevance of that information in Alzheimer’s research.ResultsIn the past 20 years, 173 publications reported results from studies with samples identified as LGBTQIA+, suggesting about six studies per year are published on cognition topic‐related biomedical literature on these populations. The bulk of the empirical articles focused on sexual risk‐taking (n = 56) with a few addressing specific medical conditions: HIV (n = 37), AD/ADRD (n = 3), and cervical cancer (n = 1). Eight articles discussed cognition, with 5 of them reporting on cognitive measures.ConclusionsBiomedical research on cognition with LGBTQIA+ populations remains focused on sexual behavior. Understanding how sexual orientation influences cognitive health and medical management requires advancing a conceptual framework of how other social and structural determinants of health operate on LGBTQIA+ identities. Investigations, for example, that help advance what is known about cognition – risks, resilience, and function, in members of SGM groups that are impacted by barriers to quality healthcare, employment instability, and experience daily discrimination. This type of framework may facilitate LGBTQIA+ inclusion in cognition studies and research priorities.
Urinary cadmium concentration and incident cognitive impairment: the REGARDS study
Authors: Zhang Yijia , Lu Liping , Bejerano Shai , Angley Meghan , Kahe Ka 
Published: December 2022

AbstractBackgroundStudies have indicated neurotoxicity of cadmium (Cd) exposure. However, little is known about Cd exposure in relation to cognitive impairment.MethodA total of 2,172 participants (mean age: 64.1±9.0 years old; female: 54.8%; Black: 38.7%), without cognitive impairment or stroke at baseline (2003‐2007), from a random sub‐cohort (n = 2,666) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, were included in this study. Urinary creatinine‐corrected Cd concentrations were measured at baseline. The Enhanced Cognitive Battery (ECB) and Six Item Screener (SIS) were performed every two years (ECB) or annually (SIS) during an average of 10 years of follow‐up. The ECB consisted of 4 tests: Word list learning (WLL), Delayed Recall (WLD), Animal Fluency, and Letter F Fluency, and its composite score was used to determine our first outcome: cognitive impairment by ECB. Because of missing data on ECB scores (n = 482), we also defined a second outcome for cognitive impairment by assigning them a cognitive impairment status based on SIS. Therefore, in the secondary analysis, the outcomes consisted of three levels: ECB, SIS, and control. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were examined using multivariable‐adjusted logistic regression for the ECB‐defined cognitive impairment or using multinomial logistic regression for the second outcome.ResultDuring the follow‐up, 53 participants developed cognitive impairment as assessed by the ECB and 36 cases were determined by the SIS. After adjustment for potential confounders, no significant association was observed between the urinary Cd concentration and incident cognitive impairment. Comparing the highest tertile of Cd concentration to the lowest, the OR (95% CI) of incident cognitive impairment was 1.07 (95% CI: 0.43, 2.67; P
for trend = 0.87) for the cases measured by ECB (Table 1). In the analysis of multinomial logistic regression, the OR (95% CI) was 1.15 (95% CI: 0.47, 2.81; P
for trend = 0.97) for ECB and 1.04 (95% CI: 0.34, 3.22; P
for trend = 0.32) for SIS (tertile 3 vs. tertile 1) (Table 2).ConclusionFindings from this US cohort do not support the hypothesis that Cd exposure is associated with the risk of cognitive impairment.
Phenotypic characterization of UCI MODEL‐AD mice using RNA‐seq
Authors: Gantuz Magdalena , Liang Heidi Yahan , Rezaie Narges , AD MODEL , Mortazavi Ali 
Published: December 2022

AbstractBackgroundThe development and characterization of new mouse models late‐onset Alzheimer’s Disease (LOAD) are critical for understanding the progression of the pathology and as a platform for theevaluation of new drugs. The UCI MODEL‐AD project focuses on the development of LOAD mouse models based on human GWAS data.MethodWe evaluate each new modeldeveloped in our group by performing a comparative network analysis of hippocampal transcriptomes in order to relate changes in expression to other phenotypic changes. As part of our standard pipeline, we test each new GWAS variant model at the ages of 4 and 12 months crossed with 5XFAD mice to regular 5XFAD mice and GWAS variant‐only mice.ResultDifferential gene expression analysis allows us to quantify the impact of the ABI3, ABCA7, PICALM and TREM2 variants on the pathology. Each model that we have analyzed have both shared as well as unique gene modules. Several variants showed less transcriptional differences compared to wild type than 5xFAD at 4 months but increase inflammation at 12 months.ConclusionRNA transcriptome analysis combined with phenotypic characterization is essential to the characterization and identification of the most appropriate LOAD mouse model.
Retention of American Indian and Alaskan Native Patients in National Alzheimer’s Coordinating Center Data
Authors: Conniff Kyle R , Gillen Daniel L. , Grill Joshua 
Published: December 2022

AbstractBackgroundIn 2016, the Administration on Community Living noted that 258,616 American Indian and Alaskan Natives (AI/AN) were over 65 years old. That number is projected to be 648,000 by 2060. This change highlights the need to better understand Alzheimer’s disease and related dementias (ADRD) in these communities through research. Retaining AI/AN populations in research will be key to avoiding bias and maximizing value.MethodWe used logistic regression to compare participant retention at the first follow‐up visit in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set, using self‐identified White participants as a reference group. We defined retention as attending the first follow‐up visit within 18 months of the initial visit. Secondary analyses assessed potential variables related to the retention of AI/AN patients using stepwise logistic regression to identify a model that minimizes Akaike Information Criteria (AIC). Potential covariates considered include cognitive status, age, independence level, sex, education, marital status, co‐participant sex, smoking status, and body mass index.ResultsAI/AN populations had significantly lower retention than the White patients, and also had the lowest point estimate for odds of retention (OR: 0.65, 95% (0.51, 0.83)) among black (0.71 (0.67, 0.76)) and Asian (0.72 (0.64, 0.81)) populations when controlling for cognitive status, age, sex, and education. Among covariates considered for the prediction model, age (x5 years; OR: 1.13 (0.99, 1.29)) and education (more retention with high education) were found to be most predictive of retention among AI/AN participants.ConclusionRetention among AI/AN individuals was significantly lower than retention among White individuals. The stepwise‐selected logistic regression model indicated that older age at baseline and greater educational attainment may be associated with better retention. While all confidence intervals include 1, that may be a precision issue with only 224 AI/AN patients not missing information for the covariates considered for the models. Regardless, improved education in AI/AN communities may improve retention of AI/AN in research. Future research will investigate retention of AI/AN populations using different definitions of race and comparing different factors across races.
Longitudinal genetic and environmental relationships between structural‐ and diffusion‐based Alzheimer’s disease neuroimaging signatures
Authors: Williams McKenna E. , Gillespie Nathan A. , Bell Tyler Reed , Dale Anders M. , Elman Jeremy A. , Eyler Lisa T. , Fennema‐Notestine Christine , Franz Carol E , Hagler Donald J. , Lyons Michael J. , McEvoy Linda K. , Neale Michael C. , Panizzon Matthew S. , Reynolds Chandra A. , Sanderson‐Cimino Mark E. , Kremen William S. 
Published: December 2022

AbstractBackgroundComposite scores of MRI‐based brain regions associated with Alzheimer’s disease (AD) pathology, commonly termed ‘AD signatures’, are tools developed to identify brain changes specific to mild AD. We found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s aided prediction of 12‐year progression to MCI beyond age and polygenic risk for AD (Williams et al., Brain Communications, 2021). Results held up after accounting for general brain age. In contrast, a cortical thickness/hippocampal volume‐based signature did not improve prediction. Given the importance of genetic influences on brain structure and AD, we examined the phenotypic and genetic relationships among diffusion and structural AD signatures and brain age, and how those relationships change across midlife and early old age.MethodOur validated thickness/volume signature, novel MD signature, and a validated brain age measure were used in biometrical twin analyses to examine phenotypic, genetic, and environmental relationships both cross‐sectionally and longitudinally across 12 years. Participants were 736 men from three waves of the Vietnam Era Twin Study of Aging (VETSA; baseline age=56.1, SD=2.6, range=51.1‐60.2). Subsequent waves were at approximately 5.7‐year intervals.ResultBoth AD signatures and brain age are heritable (56%‐72%), but each signature captured unique phenotypic and genetic variance that is also not explained by general brain aging. Genetic correlations across time within each signature were high (0.77‐0.98). Baseline MD signatures (age=56 years) predicted thickness/volume signatures over a decade later (r= ‐0.53, 95% CI: ‐0.62, ‐0.42), but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures (r= ‐0.13, 95% CI: ‐0.24, ‐0.01). Interestingly, by wave 2 (average age=62 years), the thickness/volume signature appears to have caught up with the MD signature in terms of predictive ability.ConclusionFindings lend further support to the idea that a signature based on brain microstructure captures very early AD‐related changes that are later reflected in the macrostructural signature. This MD signature explains substantial genetic variance that is consistent throughout midlife and into early old age, supporting the utility of the MD signature as a very early AD‐related neuroimaging biomarker and its potential role in clinical trials.
Identifying complement‐related proteins expression pattern of different APOE genotypes in patients with Alzheimer’s disease
Authors: Chen Guangxin 
Published: December 2022

AbstractBackgroundApolipoprotein E (APOE) gene is one of the strongest risk factors found for late‐onset Alzheimer’s disease (AD). Complement pathways are implicated in AD. The objective of this project was to examine the difference of complement related proteins expression and networks between AD and healthy control of the same genotype.MethodTwo publicly available label free quantification (LFQ) mass spectrometry brain proteomics datasets were used. The Emory cohort consisted of 4,774 protein groups for 10 controls (E3/E3) and 24 autopsy‐confirmed AD (8 of each genotype of E2/E3, E3/E3, and E3/E4); the Banner cohort of 5,711 protein groups for 77 controls (18 E2/E3 and 59 E3/E3) and 44 autopsy‐confirmed AD (6 E2/E3, 30 E3/E3, and 8 E4/E4). Each proteomics dataset was screened by a list of complement‐related proteins identified in Uniprot database using “Complement protein” as the keyword. Differential analyses were conducted using R package DEP for AD compared to control (non‐AD) group with the same genotype. Correlation analysis using R package WGCNA (Weighted correlation network analysis) was performed to cluster similar proteins into modules. The identified modules are then correlated with APOE genotypes, tau tangle burden and neurotic amyloid plaque burden. Finally, protein functional enrichment analysis was conducted using DAVID (DAVID Bioinformatics Resources 6.8).ResultComplement proteins are highly expressed in AD (n = 36) than controls (n = 64) in genotype of E3/E3 and in AD (n = 17) than controls (n = 49) in genotype of E3/E4 in the Banner cohort (p‐value < 0.05, log‐fold‐change > log[1.5]). For both cohorts, one module is identified to have a positive correlation with APOE genotypes, tau tangle burden and neurotic amyloid plaque burden (p‐value < 0.05, correlation coefficient > 0.35). Proteins in those modules were involved in classical complement pathway and immunity innate, mitochondrial ribosomal proteins, and proteins related to Alpha‐2‐macroglobulin and extracellular exosome.ConclusionOur results suggest significant differential expressions of complement‐related proteins in AD, independent of APOE genotypes. This may provide potential biomarkers and therapeutic target related to complement pathways for AD.