Browsing by Author "Mayeux, Richard"
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Item A global view of the genetic basis of Alzheimer disease(Springer Nature, 2023) Reitz, Christiane; Pericak-Vance, Margaret A.; Foroud, Tatiana; Mayeux, Richard; Medical and Molecular Genetics, School of MedicineThe risk of Alzheimer disease (AD) increases with age, family history and informative genetic variants. Sadly, there is still no cure or means of prevention. As in other complex diseases, uncovering genetic causes of AD could identify underlying pathological mechanisms and lead to potential treatments. Rare, autosomal dominant forms of AD occur in middle age as a result of highly penetrant genetic mutations, but the most common form of AD occurs later in life. Large-scale, genome-wide analyses indicate that 70 or more genes or loci contribute to AD. One of the major factors limiting progress is that most genetic data have been obtained from non-Hispanic white individuals in Europe and North America, preventing the development of personalized approaches to AD in individuals of other ethnicities. Fortunately, emerging genetic data from other regions - including Africa, Asia, India and South America - are now providing information on the disease from a broader range of ethnicities. Here, we summarize the current knowledge on AD genetics in populations across the world. We predominantly focus on replicated genetic discoveries but also include studies in ethnic groups where replication might not be feasible. We attempt to identify gaps that need to be addressed to achieve a complete picture of the genetic and molecular factors that drive AD in individuals across the globe.Item A multiethnic transcriptome for Alzheimer Disease identifies cross‐ancestry and ancestry‐specific expression profiles(Wiley, 2025-01-03) Yang, Zikun; Cieza, Basilio; Reyes-Dumeyer, Dolly; Lee, Annie J.; Dugger, Brittany N.; Jin, Lee-Way; Murray, Melissa E.; Dickson, Dennis W.; Pericak-Vance, Margaret A.; Vance, Jeffery M.; Foroud, Tatiana M.; Teich, Andrew F.; Mayeux, Richard; Tosto, Giuseppe; Neurology, School of MedicineBackground: Alzheimer’s Disease (AD) presents complex molecular heterogeneity, influenced by a variety of factors including heterogeneous phenotypic, genetic, and neuropathologic presentations. Regulation of gene expression mechanisms is a primary interest of investigations aiming to uncover the underlying disease mechanisms and progression. Method: We generated bulk RNA‐sequencing in prefrontal cortex from 565 AD brain samples (non‐Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks, and conducted differential gene expression and enrichment analyses. We sought to identify cross‐ancestry and ancestry‐specific differentially expressed genes (DEG) and pathways across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We validated our findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095). Lastly, we validated top DEG using publically‐available human single‐nucleus RNA sequencing (snRNAseq) data. Result: AD‐known genes VGF (LFC = ‐0.661, padj = 3.78) and ADAMTS2 (padj = 1.21) were consistently differentially expressed across statistical models, ethnic groups, and replicated in ROS/MAP (Figure 1). Genes from the heat shock protein (HSP) family, e.g. HSPB7 (padj = 3.78), were the top DEG, also replicated in ROS/MAP. Ethnic‐stratified analyses prioritized TNFSF14 and SPOCD1 as top DEG in Hispanic samples. Gene set enrichment analysis highlighted several significantly pathways, including “TYROBP causal network in microglia” (WP3945; padj = 1.68) and “Alzheimer Disease” (WP5124; padj = 4.24). snRNAseq validated several DEG, including VGF downregulated in neurons (padj = 1.1). Conclusion: To our knowledge, this is the largest diverse transcriptome study for AD in post‐mortem tissue. We identified perturbated genes and pathways resulting in cross‐ethnic and ethnic‐specific findings, ultimately highlighting the importance of diversity in AD investigations.Item Analysis of Copy Number Variation in Alzheimer’s Disease in a Cohort of Clinically Characterized and Neuropathologically Verified Individuals(Public Library of Science, 2012) Swaminathan, Shanker; Huentelman, Matthew J.; Corneveaux, Jason J.; Myers, Amanda J.; Faber, Kelley M.; Foroud, Tatiana; Mayeux, Richard; Shen, Li; Kim, Sungeun; Turk, Mari; Hardy, John; Reiman, Eric M.; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); NIA-LOAD/NCRAD Family Study Group; Radiology and Imaging Sciences, School of MedicineCopy number variations (CNVs) are genomic regions that have added (duplications) or deleted (deletions) genetic material. They may overlap genes affecting their function and have been shown to be associated with disease. We previously investigated the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment using Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Institute of Aging-Late Onset AD/National Cell Repository for AD (NIA-LOAD/NCRAD) Family Study participants, and identified a number of genes overlapped by CNV calls. To confirm the findings and identify other potential candidate regions, we analyzed array data from a unique cohort of 1617 Caucasian participants (1022 AD cases and 595 controls) who were clinically characterized and whose diagnosis was neuropathologically verified. All DNA samples were extracted from brain tissue. CNV calls were generated and subjected to quality control (QC). 728 cases and 438 controls who passed all QC measures were included in case/control association analyses including candidate gene and genome-wide approaches. Rates of deletions and duplications did not significantly differ between cases and controls. Case-control association identified a number of previously reported regions (CHRFAM7A, RELN and DOPEY2) as well as a new gene (HLA-DRA). Meta-analysis of CHRFAM7A indicated a significant association of the gene with AD and/or MCI risk (P = 0.006, odds ratio = 3.986 (95% confidence interval 1.490-10.667)). A novel APP gene duplication was observed in one case sample. Further investigation of the identified genes in independent and larger samples is warranted.Item APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample(MDPI, 2019-08-16) Choi, Kyu Yeong; Lee, Jang Jae; Gunasekaran, Tamil Iniyan; Kang, Sarang; Lee, Wooje; Jeong, Jangho; Lim, Ho Jae; Zhang, Xiaoling; Zhu, Congcong; Won, So-Yoon; Choi, Yu Yong; Seo, Eun Hyun; Lee, Seok Cheol; Gim, Jungsoo; Chung, Ji Yeon; Chong, Ari; Byun, Min Soo; Seo, Sujin; Ko, Pan-Woo; Han, Ji-Won; McLean, Catriona; Farrell, John; Lunetta, Kathryn L.; Miyashita, Akinori; Hara, Norikazu; Won, Sungho; Choi, Seong-Min; Ha, Jung-Min; Jeong, Jee Hyang; Kuwano, Ryozo; Song, Min Kyung; An, Seong Soo A.; Lee, Young Min; Park, Kyung Won; Lee, Ho-Won; Choi, Seong Hye; Rhee, Sangmyung; Song, Woo Keun; Lee, Jung Sup; Mayeux, Richard; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Choo, IL Han; Nho, Kwangsik; Kim, Ki-Woong; Lee, Dong Young; Kim, SangYun; Kim, Byeong C.; Kim, Hoowon; Jun, Gyungah R.; Schellenberg, Gerard D.; Ikeuchi, Takeshi; Farrer, Lindsay A.; Lee, Kun Ho; Radiology and Imaging Sciences, School of MedicineVariants in the APOE gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10-94; GT: OR = 15.87, p = 2.62 × 10-9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10-108; GT: OR = 12.63, p = 3.44 × 10-64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.Item Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians(Wiley, 2024) Ho, Pei-Chuan; Yu, Wai Haung; Tee, Boon Lead; Lee, Wan-Ping; Li, Clara; Gu, Yian; Yokoyama, Jennifer S.; Reyes-Dumeyer, Dolly; Choi, Yun-Beom; Yang, Hyun-Sik; Vardarajan, Badri N.; Tzuang, Marian; Lieu, Kevin; Lu, Anna; Faber, Kelley M.; Potter, Zoë D.; Revta, Carolyn; Kirsch, Maureen; McCallum, Jake; Mei, Diana; Booth, Briana; Cantwell, Laura B.; Chen, Fangcong; Chou, Sephera; Clark, Dewi; Deng, Michelle; Hong, Ting Hei; Hwang, Ling-Jen; Jiang, Lilly; Joo, Yoonmee; Kang, Younhee; Kim, Ellen S.; Kim, Hoowon; Kim, Kyungmin; Kuzma, Amanda B.; Lam, Eleanor; Lanata, Serggio C.; Lee, Kunho; Li, Donghe; Li, Mingyao; Li, Xiang; Liu, Chia-Lun; Liu, Collin; Liu, Linghsi; Lupo, Jody-Lynn; Nguyen, Khai; Pfleuger, Shannon E.; Qian, James; Qian, Winnie; Ramirez, Veronica; Russ, Kristen A.; Seo, Eun Hyun; Song, Yeunjoo E.; Tartaglia, Maria Carmela; Tian, Lu; Torres, Mina; Vo, Namkhue; Wong, Ellen C.; Xie, Yuan; Yau, Eugene B.; Yi, Isabelle; Yu, Victoria; Zeng, Xiaoyi; St. George-Hyslop, Peter; Au, Rhoda; Schellenberg, Gerard D.; Dage, Jeffrey L.; Varma, Rohit; Hsiung, Ging-Yuek R.; Rosen, Howard; Henderson, Victor W.; Foroud, Tatiana; Kukull, Walter A.; Peavy, Guerry M.; Lee, Haeok; Feldman, Howard H.; Mayeux, Richard; Chui, Helena; Jun, Gyungah R.; Ta Park, Van M.; Chow, Tiffany W.; Wang, Li-San; Medical and Molecular Genetics, School of MedicineIntroduction: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. Methods: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. Results: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. Discussion: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. Highlights: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.Item Asian Cohort for Alzheimer’s Disease (ACAD) Study on Genetic and Non‐Genetic Risk Factors for Alzheimer’s Disease among Asian Americans and Canadians(Wiley, 2025-01-09) Wang, Li-San; Ho, Pei-Chuan; Tee, Boon Lead; Li, Clara; Gu, Yian; Yokoyama, Jennifer S.; Reyes-Dumeyer, Dolly; Faber, Kelley M.; Lee, Wan-Ping; Song, Yeunjoo E.; Tzuang, Marian; Vardarajan, Badri N.; Yang, Hyun-Sik; Choi, Yun-Beom; Feldman, Howard H.; Grill, Joshua D.; Henderson, Victor W.; Hsiung, Ging-Yuek Robin; Mayeux, Richard; Rosen, Howard J.; Varma, Rohit; Foroud, Tatiana M.; Kukull, Walter A.; Peavy, Guerry M.; Lee, Haeok; Yu, W. Haung; Chui, Helena C.; Jun, Gyungah R.; Park, Van Ta; Chow, Tiffany W.; The Asian Cohort for Alzheimer’s Disease Study; Medicine, School of MedicineBackground: Asian Americans and Asian Canadians (ASACs) are the fastest growing minority group in the US and Canada. However, ASACs are under‐sampled in Alzheimer’s disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer’s Disease (ACAD), the first large dementia genetics cohort focusing on Chinese, Korean, and Vietnamese, launched in 2021 to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and diverse cultural and scientific training backgrounds: both are critical in leading AD and CBPR research. Method: Upon receipt of an NIA U19 grant in 2023, ACAD has expanded to 9 recruiting sites (7 US and 2 Canadian), a coordinating site, and an analysis site with a centralized data management system. ACAD developed a comprehensive study protocol including community outreach and recruitment strategies, the data collection packet (DCP), pre‐screening and sample collection procedures, and in English, Chinese (Mandarin and Cantonese), Korean, and Vietnamese. To ensure consistency, ACAD implemented a training curriculum for data/sample collect and for culturally appropriate recruitment approaches in collaboration with community partners, clinics, and nursing homes serving Asian communities. Result: As of December 2023, more than 2,400 people expressed interests in ACAD. A total of 683 of the 899 consented participants completed DCP data into the REDCap (604 Chinese, 54 Korean, and 25 Vietnamese), while 399 saliva samples and 285 blood samples were received. Participants aged 60 –103 years at enrollment, 67% were female, and 47% reported having a college or above education. Currently, ACAD is revising the study protocol in response to feedback received in its pilot phase, including the need to include additional neuropsychological tests and cultural tailored lifestyle questionnaires with an emphasis on immigration experiences. Conclusion: The ACAD team (including community partners) have learned valuable lessons and demonstrated the feasibility of recruiting ASACs in clinical research. With an expansion plan and in collaboration with other AD research focuses on racial minority populations, insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD.Item Association of dietary fatty acids with longitudinal change in plasma-based biomarkers of Alzheimer’s disease(Elsevier, 2025) Hoost, Serena S.; Honig, Lawrence S.; Kang, Min Suk; Bahl, Aanya; Lee, Annie J.; Sanchez, Danurys; Reyes-Dumeyer, Dolly; Lantigua, Rafael A.; Dage, Jeffrey L.; Brickman, Adam M.; Manly, Jennifer J.; Mayeux, Richard; Gu, Yian; Neurology, School of MedicineBackground: Elevated intake of omega-3 polyunsaturated fatty acids is linked to a reduced risk of dementia in some prospective studies. However, few studies have examined the relationship between nutrient intake and plasma biomarkers of Alzheimer's disease. Objectives: We explored whether omega-3, omega-6, and monounsaturated fat intakes were associated with changes in plasma biomarkers of Alzheimer's disease over time. Design: The Washington Heights-Inwood Columbia Aging Project is a prospective cohort study (1994-2021); the data set used here includes a mean follow-up of 7.0 years. Setting: Community-based in New York City. Participants: 599 dementia-free individuals at baseline who completed a 61-item food frequency questionnaire and had biomarkers measured in plasma from at least two different time points. Measurements: Fatty acid intake tertiles were computed from participant-completed 61-item Willett semi-quantitative food frequency questionnaires (Channing Laboratory, Cambridge, Massachusetts) obtained once at their baseline visit. Plasma-based biomarker assays were performed, using the single molecule array technology Quanterix Simoa HD-X platform, at baseline and follow-up visits. Generalized Estimating Equations (GEE) models were used to evaluate the association between baseline nutrient intake tertile and changes in biomarkers including phospho-tau181, amyloid-beta 42/40 ratio, phospho-tau181/amyloid-beta42 ratio, glial fibrillary acidic protein, neurofilament light chain, and two biomarker patterns derived from Principal Component Analysis (PCA1 and PCA2), with higher scores indicating a high level of neurodegeneration and low level of Alzheimer's disease burden, respectively). Models were adjusted for age, sex, race/ethnicity, education, and calculated total energy intake initially, and additionally for cerebrovascular risk factors. Results: Higher baseline omega-3 intake tertile was associated with lesser decline in PCA2 (β = 0.221, p < 0.001) and amyloid-beta 42/40 ratio (β = 0.022, p = 0.003), and a lesser rise in phospho-tau181 (β = -0.037, p = 0.001). Higher omega-6 intake tertile was linked to a lesser rise in phospho-tau181 (β = -0.050, p < 0.001) and glial fibrillary acidic protein (β = -0.028, p = 0.002). Most associations persisted after adjusting for cardiovascular risk factors. Conclusions: Higher relative baseline intake of omega-3 and omega-6 fatty acids is associated with lesser progression of blood-based biomarkers of Alzheimer's disease. Consuming healthy fatty acids may help prevent accumulation of Alzheimer's disease-related pathological changes.Item Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals(American Medical Association, 2015-11) Ghani, Mahdi; Reitz, Christiane; Cheng, Rong; Vardarajan, Badri Narayan; Jun, Gyungah; Sato, Christine; Naj, Adam; Rajbhandary, Ruchita; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick A.; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Lee, Joseph H.; Schellenberg, Gerard D.; St. George-Hyslop, Peter; Mayeux, Richard; Rogaeva, Ekaterina; Department of Psychiatry, IU School of MedicineIMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.Item Beyond GWAS: Investigating Structural Variants and Their Segregation in Familial Alzheimer’s Disease(Wiley, 2025-01-09) Gunasekaran, Tamil Iniyan; Reyes-Dumeyer, Dolly; Corvelo, André; Clarke, Wayne E.; Evani, Uday S.; Byrska-Bishop, Marta S.; Basile, Anna O.; Runnels, Alexi; Musunuri, Rajeeva O.; Narzisi, Giuseppe; Faber, Kelley M.; Goate, Alison M.; Boeve, Brad F.; Cruchaga, Carlos; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Rosenberg, Roger N.; Tsuang, Debby W.; Rivera Mejia, Diones; Medrano, Martin; Lantigua, Rafael A.; Sweet, Robert; Bennett, David A.; Wilson, Robert S.; Foroud, Tatiana M.; Dalgard, Clifton L.; Mayeux, Richard; Zody, Michael; Vardarajan, Badri N.; Medical and Molecular Genetics, School of MedicineBackground: Late‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated. Method: We analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset. Result: We identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene. Conclusion: Our findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.Item Blood‐Based Biomarkers to Aid in Alzheimer’s Disease Prediction or Diagnosis: Analysis in a Multi‐Ethnic Cohort Study(Wiley, 2025-01-03) Bahl, Aanya; Honig, Lawrence S.; Kang, Min Suk; Sanchez, Danurys; Reyes-Dumeyer, Dolly; Manly, Jennifer J.; Lantigua, Rafael A.; Dage, Jeffrey L.; Brickman, Adam M.; Vardarajan, Badri N.; Mayeux, Richard; Gu, Yian; Neurology, School of MedicineBackground: Blood‐based biomarkers may aid in the diagnosis of Alzheimer’s Disease (AD), but their contribution may be confounded by the presence of multiple chronic conditions and have not been well‐tested in community populations. In the current study, we aimed to determine whether blood‐based biomarkers can aid in refining a multi‐ethnic, urban clinically diagnosed AD community‐based cohort. Method: We included 546 individuals in the Washington Heights, Hamilton Heights, and Inwood Columbia Aging Project (WHICAP) study in this cross‐sectional study. Six biomarkers, including phosphorylated‐tau‐181 (P‐tau181), total (T‐tau), amyloid‐beta 40 and 42 (Aβ40, Aβ42), Glial Fibrillary Acid Protein (GFAP), and Neurofilament Light Chain (NfL) were measured using Quanterix SIMOA HD‐X platforms. The association between the biomarkers and AD or cognitive impairment was tested using logistic regression, adjusted for age, sex, ethnic group, and years of education. Individuals were subsequently characterized as ‘biomarker positive’ or ‘biomarker negative’ based on combined GFAP and P‐tau181/Aβ42 cut scores. Result: The mean age of individuals was 79.3 years (6.56) and 379 (69.4%) were women, 133 (24.48%), were Non‐Hispanic Black, 153 (28.0%) Non‐Hispanic White, and 248 (45.4%) were Hispanic. A clinical diagnosis of AD was made in 129 (25.49%) individuals. Low Aβ42 (OR = 0.18, [95% CI: 0.04 ‐ 0.92]), low Aβ42/Aβ40 (OR = 0.49, [95% CI: 0.228 ‐ 0.872), and high P‐tau181/Ab42 (OR = 5.494, [95% CI: 1.523 – 20.416]) were associated with a clinical diagnosis of AD suggesting a role as predictive biomarkers. However, the best combination, GFAP and P‐tau181/Aβ42 cut scores, yielded a sensitivity of 41% and specificity of 70.5% for clinically diagnosed AD. The concordance was 54.5% and the discordance was present in both directions. Low education, cardiovascular and other comorbidities might contribute to the discrepancy between biomarker positivity and clinical diagnosis. Conclusion: While GFAP and P‐tau181/Aβ42 levels are associated with AD pathology and can aid in the diagnosis of AD, the presence of multiple chronic conditions may lead to either false positives or negatives. Large multi‐ethnic community cohort studies are needed to further examine the utility of these biomarkers in aiding in the clinical diagnosis of AD.