Causal association of cognitive reserve on Alzheimer's disease with putative sex difference

Hao Wang, Brin Sara Rosenthal, Carolina Makowski, Min Tzu Lo, Ole A. Andreassen, Rany M. Salem, Linda K. McEvoy, Mark Fiecas, Chi Hua Chen

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Introduction: 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.

Original languageEnglish (US)
Article numbere12270
JournalAlzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
Issue number1
StatePublished - 2021

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health R56AG061163, R01MH118281; The Alzheimer's Disease Genetics Consortium (ADGC) were supported by a grant from the National Institute on Aging/National Institutes of Health UO1AG032984 and complete acknowledgments for ADGC are detailed on the ADGC website ( ).

Publisher Copyright:
© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.


  • Alzheimer's disease
  • Mendelian randomization
  • causality
  • cognitive performance
  • cognitive reserve
  • educational attainment
  • genomic structural equation modeling
  • intelligence
  • network analysis
  • polygenic risk score
  • sex differences


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