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

doi:10.1002/dad2.12270

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

Biostatistics

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

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 language	English (US)
Article number	e12270
Journal	Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
Volume	13
Issue number	1
DOIs	https://doi.org/10.1002/dad2.12270
State	Published - 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 ( http://www.adgenetics.org/content/acknowledgements ).

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

Keywords

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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10.1002/dad2.12270

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title = "Causal association of cognitive reserve on Alzheimer's disease with putative sex difference",

abstract = "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.",

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

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

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 ( http://www.adgenetics.org/content/acknowledgements ). Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.",

year = "2021",

doi = "10.1002/dad2.12270",

language = "English (US)",

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T1 - Causal association of cognitive reserve on Alzheimer's disease with putative sex difference

AU - Wang, Hao

AU - Rosenthal, Brin Sara

AU - Makowski, Carolina

AU - Lo, Min Tzu

AU - Andreassen, Ole A.

AU - Salem, Rany M.

AU - McEvoy, Linda K.

AU - Fiecas, Mark

AU - Chen, Chi Hua

N1 - 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 ( http://www.adgenetics.org/content/acknowledgements ). Publisher Copyright: © 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

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KW - Mendelian randomization

KW - causality

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KW - cognitive reserve

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KW - genomic structural equation modeling

KW - intelligence

KW - network analysis

KW - polygenic risk score

KW - sex differences

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

Abstract

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