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

Alzheimers Dement. 2024 Feb;20(2):1268-1283. doi: 10.1002/alz.13508. Epub 2023 Nov 20.

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.

Keywords: Alzheimer's disease; GWAS; genetics; memory.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / genetics
  • Cognition
  • Endophenotypes
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Humans
  • Memory Disorders / genetics
  • Polymorphism, Single Nucleotide / genetics

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