Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease

• Published in: Alzheimer's & dementia Vol. 20; no. 2; pp. 1268 - 1283
• Main Authors: Archer, Derek B., Eissman, Jaclyn M., Mukherjee, Shubhabrata, Lee, Michael L., Choi, Seo‐Eun, Scollard, Phoebe, Trittschuh, Emily H., Mez, Jesse B., Bush, William S., Kunkle, Brian W., Naj, Adam C., Gifford, Katherine A., Cuccaro, Michael L., Pericak‐Vance, Margaret A., Farrer, Lindsay A., Wang, Li‐San, Schellenberg, Gerard D., Mayeux, Richard P., Haines, Jonathan L., Jefferson, Angela L., Kukull, Walter A., Keene, C. Dirk, Saykin, Andrew J., Thompson, Paul M., Martin, Eden R., Bennett, David A., Barnes, Lisa L., Schneider, Julie A., Crane, Paul K., Dumitrescu, Logan, Hohman, Timothy J.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2024
• Subjects: Aging; Alzheimer's disease; Arrays; Chromosomes; Cognitive ability; Consortia; Dementia; Executive function; Genes; genetics; Genomes; Genomics; GWAS; Heritability; Hispanic Americans; Longitudinal studies; Memory; Neuropsychology; Quality control; Research centers; Review boards; Variants; GWAS; genetics; memory; Alzheimer's disease
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.13508

INTRODUCTION Although large‐scale genome‐wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. METHODS We conducted a cross‐ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. RESULTS We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non‐Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene‐level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD‐related traits, neuropsychiatric traits, and autoimmune traits. DISCUSSION We discovered several novel loci, genes, and genetic correlations associated with late‐life memory performance and decline. Highlights Late‐life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late‐life memory. We identified four novel genes associated with late‐life memory. Late‐life memory shares genetic architecture with psychiatric/autoimmune traits.