Genetic predictors of multiple cognitive domains within ancestry groups in older adults
Authors: Walters Skylar , 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. , Cruchaga Carlos , Pericak‐Vance Margaret A , Farrer Lindsay A. , Wang Li‐San , Haines Jonathan L. , Jefferson Angela L. , Kukull Walter A. , Keene C Dirk , Saykin Andrew J. , Thompson Paul M , Martin Eden R. , Bennett David A. A , Barnes Lisa L. , Schneider Julie A , Crane Paul K , Albert Marilyn S. , Johnson Sterling C , Engelman Corinne D. , Mayeux Richard , Vardarajan Badri N , Hohman Timothy J. , Dumitrescu Logan C ,   The Alzheimer’s Disease Neuroimaging Initiative (ADNI)Alzheimer’s Disease Genetics Consortium (ADGC)The Alzheimer’s Disease Sequencing Project (ADSP)
Published: December 2023

Background

Alzheimer’s disease (AD) is clinically characterized by disabling cognitive impairment, though substantial variability in cognitive symptoms and trajectories is observed in AD individuals. However, genetic predictors of domain‐specific cognitive performance remain undiscovered. We investigated cross‐sectional and longitudinal genetic architecture of harmonized memory, executive function, and language scores within and across ancestry groups.

Method

Using data from 7 cohorts of cognitive aging and AD, individuals >60 years at baseline were included (mean age at baseline = 71.2). Cognitive scores for memory, executive function, and language were harmonized using latent variable models. Slopes for cognitive scores were calculated for each domain with linear mixed‐effects models. GWAS was performed on each cognitive domain for individual cohorts, both at baseline and longitudinally. Models covaried for baseline age, sex, and the first three genetic principal components. Individual models were assessed among non‐Hispanic Whites (NHW) (N = 26,455), non‐Hispanic Blacks (NHB) (N = 3,410), and cross‐ancestry (NHW + NHB) (N = 29,865). Results were meta‐analyzed across cohorts.

Result

We identified six genetic loci showing a genome‐wide significant effect on cognition, in addition to well‐established associations between cognition and APOE: three loci in NHW, one locus in NHB, and two loci in cross‐ancestry results. In NHW, a chromosome 2 locus (rs6733839) near BIN1, a previously reported AD risk gene, was associated with longitudinal memory performance (MAF = 0.40, p = 3.36E‐08). Additionally, in NHW, two chromosome 2 loci (rs2940785 and rs2972059) were associated with memory decline (MAF = 0.05, = 3.92E‐09; MAF = 0.05, p = 5.06E‐09, respectively). Despite the small sample size, a chromosome 10 locus (rs77595416) was associated with longitudinal executive function in NHB (MAF = 0.01, p = 7.68E‐09). When analyzing cross‐ancestry results, two chromosome 2 loci near BIN1 (rs4663105 and rs6733839) were associated with memory decline (MAF = 0.44, p = 2.65E‐08; MAF = 0.40, p = 9.48E‐10, respectively).

Conclusion

We elucidate novel and replicate known genetic predictors of domain‐specific cognition in older adults. Furthermore, we show that genetic architecture of multiple cognitive domains in older adults differs by ancestry, highlighting SNPs observed in longitudinal memory (NHW and cross‐ancestry) and executive function (NHB). While replication is warranted, our results underscore the contribution of genetic predictors beyond APOE to cognitive decline and suggest the importance of ancestry‐specific analyses of cognition.