Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease
Derek B. Archer, Jaclyn M. Eissman, Shubhabrata Mukherjee, Michael L. Lee, Seo‐Eun Choi, Phoebe Scollard, Emily H. Trittschuh, Jesse Mez, William S. Bush, Brian W. Kunkle, Adam C. Naj, Katherine A. Gifford, The Alzheimer's Disease Neuroimaging Initiative (ADNI), The Alzheimer's Disease Sequencing Project (ADSP), Michael L. Cuccaro, Margaret A. Pericak‐Vance, Lindsay A. Farrer, Weixin Wang, Gerard D. Schellenberg, Richard Mayeux, Jonathan L. Haines, Angela L. Jefferson, Walter A. Kukull, C. Dirk Keene, Andrew J. Saykin, Paul M. Thompson, Eden R. Martin, David A. Bennett, Lisa L. Barnes, Julie A. Schneider, Paul K. Crane, Logan Dumitrescu, Timothy J. Hohman
Abstract
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.