Evidence map›Paper›PMID 35552371›Full record

ArticleBrain : a journal of neurology2022

Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.

Jaclyn M Eissman, Logan Dumitrescu, Emily R Mahoney, Alexandra N Smith, Shubhabrata Mukherjee, Michael L Lee, Phoebe Scollard, Seo Eun Choi, William S Bush, Corinne D Engelman and 44 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
75citing papers in PubMed, 2 pooled it
9.8field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

75 citing papers in PubMed, 2 syntheses or guidelines pooled it, 93 citations in OpenAlex.

  1. Sex-stratified genome-wide meta-analysis identifies novel loci for cognitive decline in older adults.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Pooled it
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  8. Genetic architecture of the limbic white matter microstructure in aging and Alzheimer's Disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Article
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  17. Single-cell landscape of sex-specific drivers of Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  18. Article
  19. Genetic regulation of the metabolome differs by sex, Alzheimer's disease stage, and plasma biomarker status.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  20. Article

15 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

54 authors at 20 institutions in 2 countries.

Jaclyn M EissmanVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.ORCID 0000-0001-6439-3999
Logan DumitrescuVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.ORCID 0000-0002-9782-9944
Emily R MahoneyVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Alexandra N SmithVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Shubhabrata MukherjeeDepartment of Medicine, University of Washington, Seattle, WA, USA.
Michael L LeeDepartment of Medicine, University of Washington, Seattle, WA, USA.ORCID 0000-0002-3112-1214
Phoebe ScollardDepartment of Medicine, University of Washington, Seattle, WA, USA.
Seo Eun ChoiDepartment of Medicine, University of Washington, Seattle, WA, USA.
William S BushCleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.ORCID 0000-0002-9729-6519
Corinne D EngelmanDepartment of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Qiongshi LuDepartment of Statistics, University of Wisconsin-Madison, Madison, WI, USA.ORCID 0000-0002-4514-0969
David W FardoDepartment of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
Emily H TrittschuhDepartment of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Jesse MezDepartment of Neurology, Boston University School of Medicine, Boston, MA, USA.
Catherine C KaczorowskiThe Jackson Laboratory, Bar Harbor, ME, USA.
Hector Hernandez SaucedoUC Davis Alzheimer's Disease Research Center, Department of Neurology, University of California Davis Medical Center, Sacramento, CA, USA.
Keith F WidamanUniversity of California at Riverside, Riverside, CA, USA.
Rachel F BuckleyDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-5356-5537
Michael J ProperziDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Elizabeth C MorminoDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Hyun Sik YangDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Theresa M HarrisonHelen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
Trey HeddenIcahn School of Medicine at Mount Sinai, New York City, NY, USA.
Kwangsik NhoDepartment of Radiology and Imaging Sciences, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Shea J AndrewsIcahn School of Medicine at Mount Sinai, New York City, NY, USA.ORCID 0000-0002-1921-9470
Douglas TommetDepartment of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, RI, USA.
Niran HadadThe Jackson Laboratory, Bar Harbor, ME, USA.
R Elizabeth SandersDepartment of Medicine, University of Washington, Seattle, WA, USA.
Douglas M RuderferVanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Katherine A GiffordVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Xiaoyuan ZhongDepartment of Statistics, University of Wisconsin-Madison, Madison, WI, USA.
Neha S RaghavanDepartment of Neurology, Columbia University, New York, NY, USA.
Badri N VardarajanDepartment of Neurology, Columbia University, New York, NY, USA.
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Alzheimer’s Disease Genetics Consortium (ADGC)
A4 Study Team
Margaret A Pericak-VanceJohn P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
Lindsay A FarrerDepartment of Neurology, Boston University School of Medicine, Boston, MA, USA.
Li San WangPenn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Carlos CruchagaDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Gerard D SchellenbergPenn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Nancy J CoxVanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Jonathan L HainesCleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
C Dirk KeeneDepartment of Pathology, University of Washington, Seattle, WA, USA.
Andrew J SaykinDepartment of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
Eric B LarsonDepartment of Medicine, University of Washington, Seattle, WA, USA.
Reisa A SperlingDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Richard MayeuxDepartment of Neurology, Columbia University, New York, NY, USA.
Michael L CuccaroJohn P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.ORCID 0000-0003-3689-554X
Julie A SchneiderRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Paul K CraneDepartment of Medicine, University of Washington, Seattle, WA, USA.
Angela L JeffersonVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Timothy J HohmanVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
University of Washington · USVanderbilt University Medical Center · USRush University Medical Center · USBoston University · USHarvard University · USNewYork–Presbyterian Hospital · USUniversity of Wisconsin–Madison · USBrigham and Women's Hospital · USCase Western Reserve University · USIcahn School of Medicine at Mount Sinai · USIndiana University School of MedicineJackson Laboratory · USUniversity of Miami · USBrown University · USKaiser Permanente Washington Health Research Institute · USStanford University · USUniversity of California, Berkeley · USUniversity of California Davis Medical Center · USUniversity of California, Riverside · USUniversity of Kentucky · US

Funding

Alzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
Translational pharmacoepidemiology: neuroprotection and neurotoxicity of antihypertensives and strong anticholinergicsU19AG066567 · NIA · KAISER FOUNDATION RESEARCH INSTITUTE · PI CHRISTOPHER DIRK KEENE · 2021 to 2026
$80.4M
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
THERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI GRABOWSKI, THOMAS J. · 1985 to 2019
$57.2M
SUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6M
SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1M
EPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3M
THE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITEU24AG041689 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LI-SAN WANG · 2012 to 2026
$42.3M
The Vanderbilt Institute for Clinical and Translational Research (VICTR)UL1TR000445 · NCATS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BERNARD, GORDON RAPHAEL · 2012 to 2016
$41.4M
Furthering scientific understanding of mechanisms underlying resilience to the effects of AD pathology by incorporating state of the art quantification of gliosis, inflammation, & synaptic toxicityU01AG006781 · NIA · UNIVERSITY OF WASHINGTON · PI CRANE, PAUL K, LARSON, ERIC B · 1986 to 2020
$39.3M
MVP Data Integration into the ADSP Phenotype Harmonization ConsortiumU24AG074855 · NIA · VANDERBILT UNIVERSITY MEDICAL CENTER · PI CUCCARO, MICHAEL L, HOHMAN, TIMOTHY J · 2021 to 2025
$37.5M
NCATS NIH HHS UL1 TR000445NIA NIH HHS F31 AG051381NIA NIH HHS F31 AG077791NIA NIH HHS K01 AG049164NIA NIH HHS K23 AG062750NIA NIH HHS K24 AG046373NIA NIH HHS P01 AG002219NIA NIH HHS P01 AG017216NIA NIH HHS P20 AG068082NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG066509NIA NIH HHS P30 AG072975NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG016574NIA NIH HHS R00 AG061238NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG018023NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG034962NIA NIH HHS R01 AG046171NIA NIH HHS R01 AG056534NIA NIH HHS R01 AG057914NIA NIH HHS R01 AG059716NIA NIH HHS R01 AG061518NIA NIH HHS R01 AG063689NIA NIH HHS R01 AG073439NIA NIH HHS R01 AG074012NIA NIH HHS R13 AG030995NIA NIH HHS R21 AG059941NIA NIH HHS R56 AG057191NIA NIH HHS RF1 AG051550NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG024904NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356NIA NIH HHS U01 AG068057NIA NIH HHS U19 AG066567NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG041689NIA NIH HHS U24 AG074855NICHD NIH HHS K12 HD043483NIDA NIH HHS HHSN271201300031CNIGMS NIH HHS T32 GM080178NIH HHS S10 OD023680NIMH NIH HHS P50 MH066392NIMH NIH HHS P50 MH084051NIMH NIH HHS P50 MH084053NIMH NIH HHS P50 MH096891NIMH NIH HHS R01 MH075916NIMH NIH HHS R01 MH085542NIMH NIH HHS R01 MH093725NIMH NIH HHS R01 MH097276NIMH NIH HHS R01 MH109677NIMH NIH HHS R01 MH109897NIMH NIH HHS R01 MH110921NIMH NIH HHS R37 MH057881NIMH NIH HHS U01 MH103392NINDS NIH HHS R01 NS080820NINDS NIH HHS R01 NS100980NINDS NIH HHS U24 NS072026
6 · The paper itself

Abstract

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.

Indexed as

Alzheimer DiseaseCognitive DysfunctionMultiple SclerosisCognitionFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMaleSex CharacteristicsAlzheimer’s diseasegeneticsGWASresiliencesex differences

Identifiers

PMID35552371
PMCPMC9337804
OpenAlexW4280540548

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.