Year: 2025
Type: article
Study design: Observational Study
Abstract: Background Hippocampal volume is an important in vivo imaging marker for Alzheimer's disease (AD) risk and progression. Reported sex differences show accelerated hippocampal atrophy in females compared to males as AD‐related pathology increases. However, genome‐wide association studies (GWAS) of hippocampal volume have been mainly conducted in mid‐life participants with no AD pathology and have not been systemically examined for sex‐specific genetic effects. We investigated the sex‐specific genetic architecture of hippocampal volume in eight aging and AD cohorts. Method This study included 5,523 non‐Hispanic White participants (N Males =2,549; N Females =2,974; mean baseline age=72 yrs; mean number of visits=2.3; 32.8% cognitively impaired). Hippocampal volume and estimated total intracranial volume (eTIV) were segmented from T 1 ‐weighted MRIs using Hippodeep. Total hippocampal volume (Left+Right) and eTIV were harmonized using neuroCombat in R. Longitudinal slopes for hippocampal volume were calculated with linear mixed‐effects models. GWAS were performed, at baseline and longitudinally, by cohort in all participants, sex‐stratified, and sex‐interaction models. Models covaried for baseline age, sex (in all participants), eTIV, and the first five genetic principal components. Longitudinal models also covaried for diagnosis conversion over time. Results were meta‐analyzed across cohorts. Results We identified three genome‐wide significant genetic loci associated with hippocampal volume. Specifically, a chromosome 6 locus (index SNP rs62434269; MAF=0.33) near ARID1B was associated at baseline in all participants (β=0.10, p = 3.54x10 ‐8 ) (Figure 1). Further, we found a locus on chromosome 8 (rs34173062; MAF=0.09), which is a previously reported AD risk variant and eQTL for SHARPIN (β=‐0.22, p = 1.68E‐09), with significant effects in males (β Males =‐0.32, p Males =2.14x10 ‐9 ) but not females (β Females =‐0.11, p Females =0.03; p sex‐interaction =0.004) (Figure 2A‐B). A chromosome 14 locus (rs75592630; MAF=0.05) near AKAP6 , a gene previously associated with cognition, was associated with hippocampal volume change over time in females (β Females =‐0.28, p Females =1.19x10 ‐9 ) but not males (β Males =‐0.01, p Males =0.79; p sex‐interaction =0.003) (Figure 2C‐D). Conclusion We extend findings of a previously reported AD risk variant near SHARPIN to hippocampal volume and provide evidence of novel sex‐specific genetic effects. While replication is warranted, our results suggest the importance of genetic predictors and sex differences on imaging biomarkers.
Source: Alzheimer s & Dementia
Authors: Skylar Walters, Derek B. Archer, Kwangsik Nho, Andrew J. Saykin, Christos Davatzikos, Guray Erus, Shannon L Risacher, Mohamad Habes, Di Wang, Reisa A. Sperling, Mohamad J. Alshikho, Adam Brickman, Marilyn S. S. Albert, Anja Soldan, Yang An, Lori L Beason‐Held, Murat Bilgel, Susan M. Resnick, Toshiko Tanaka, Keenan A. Walker, Sarah Biber, Walter W. Kukull, Lisa L. Barnes, David A. A. Bennett, Philip L. De Jager, Vilas Menon, Julie A Schneider, Corinne D. Engelman, Jason M Fletcher, Sterling C Johnson, Qiongshi Lu, Jie Song, L. Taylor Davis, Mary Ellen I. Koran, Dandan Liu, Kimberly R. Pechman, Niranjana Shashikumar, Angela L. Jefferson, Timothy J. Hohman, Logan Dumitrescu, The Alzheimer's Disease Neuroimaging Initiative (ADNI); The Alzheimer's Disease Sequencing Project (ADSP)
Institutions: Vanderbilt University Medical Center, Indiana University School of Medicine, Indiana University Indianapolis, University of Pennsylvania, The University of Texas at San Antonio Health Science Center, Harvard University, Massachusetts General Hospital, Columbia University, Johns Hopkins University, Johns Hopkins Medicine, National Institutes of Health, National Institute on Aging, University of Washington, Rush University Medical Center, Columbia University Irving Medical Center, University of Wisconsin–Madison, Vanderbilt University
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
OpenAlex ID: W7117321433
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