Open AccessCausal association of cognitive reserve on Alzheimer's disease with putative sex difference
Author(s) -
Wang Hao,
Rosenthal Brin Sara,
Makowski Carolina,
Lo MinTzu,
Andreassen Ole A.,
Salem Rany M.,
McEvoy Linda K.,
Fiecas Mark,
Chen ChiHua
Publication year - 2021
Publication title -
alzheimer's and dementia: diagnosis, assessment and disease monitoring
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.497
H-Index - 37
ISSN - 2352-8729
DOI - 10.1002/dad2.12270
Subject(s) - mendelian randomization , genome wide association study , cognition , pleiotropy , disease , biology , genetic architecture , causality (physics) , genetic association , association (psychology) , alzheimer's disease , cognitive decline , causal inference , psychology , genetics , developmental psychology , dementia , gene , single nucleotide polymorphism , medicine , neuroscience , phenotype , genotype , genetic variants , pathology , psychotherapist , physics , quantum mechanics
Sex‐dependent risk factors may underlie sex differences in Alzheimer's disease (AD). Methods Using sex‐stratified genome‐wide association studies (GWAS) of AD, we evaluated associations of 12 traits with AD through polygenic risk scores (PRS) and Mendelian randomization (MR), and explored joint genetic architecture among significant traits by genomic structural equation modeling and network analysis. Results AD was associated with lower PRS for premorbid cognitive performance, intelligence, and educational attainment. MR showed a causal role for the cognition‐related traits in AD, particularly among females. Their joint genetic components encompassed RNA processing, neuron projection development, and cell cycle pathways that overlap with cellular senescence. Cholesterol and C‐reactive protein showed pleiotropy but no causality with AD. Discussion Lower cognitive reserve is causally related to AD. The stronger causal link between cognitive performance and AD in females, despite similar PRS between sexes, suggest these differences may result from gene–environmental interactions accumulated over the lifespan.