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

Author(s): Archer, DB; Eissman, JM; Mukherjee, S; Lee, ML; Choi, S; Scollard, P; Trittschuh, EH; Mez, JB; Bush, WS; Kunkle, BW; Naj, AC; Gifford, KA; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer's Disease Genetics Consortium (ADGC); Alzheimer's Disease Sequencing Project (ADSP); Cuccaro, ML; Pericak-Vance, MA; Farrer, LA; Wang, L; Schellenberg, GD; Mayeux, RP; Haines, JL; Jefferson, AL; Kukull, WA; Keene, CD; Saykin, AJ; Thompson, PM; Martin, ER; Bennett, DA; Barnes, LL; Schneider, JA; Crane, PK; Dumitrescu, L; Hohman, TJ;
Year: 2024;  
Journal: Alzheimer's & Dementia: The Journal of the Alzheimer's Association;  
Volume: 20;  
Issue: 2;  

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.