ArticleTranslational psychiatry2022
Polygenic resilience scores capture protective genetic effects for Alzheimer's disease.
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Article in Translational psychiatry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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20citing papers in PubMed, 1 pooled it
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20 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Meta-Analysis of Transcriptomic Studies of Blood and Six Brain Regions Identifies a Consensus of 15 Cross-Tissue Mechanisms in Alzheimer's Disease and Suggests an Origin of Cross-Study Heterogeneity.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2025Pooled it
- Polygenic risk scores in human genetics for study design discovery and translation.Human genetics · 2026Review
- A novel method to disentangle tightly linked risk and resilience genes for brain disorders: application to Alzheimer's disease.Molecular psychiatry · 2026Article
- Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.EBioMedicine · 2026Article
- A roadmap for conducting more inclusive research on brain resilience in ageing and dementia.Nature reviews. Neuroscience · 2026Review
- Alzheimer's disease: genetic background in the era of next-generation sequencing technologies.Brain communications · 2026Review
- Genetic resilience to chronic obstructive pulmonary disease is a clinically distinct subtype in individuals with cigarette smoke exposure.Respiratory research · 2025Article
- Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.Research square · 2025Article
- Polygenic risk for Alzheimer's disease in healthy aging: age-related and APOE-driven effects on brain structures and cognition.Genome medicine · 2025Article
- GRPa-PRS: A risk stratification method to identify genetically-regulated pathways in polygenic diseases.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Association of rareJournal of Alzheimer's disease : JAD · 2025Article
- Neuroimaging Predictors of Cognitive Resilience against Alzheimer's Disease Pathology.Annals of neurology · 2025Article
- Protective genetic variants against Alzheimer's disease.The Lancet. Neurology · 2025Review
- Scrutinizing neurodegenerative diseases: decoding the complex genetic architectures through a multi-omics lens.Human genomics · 2024Review
- Review
- Alzheimer's disease protective allele ofmedRxiv : the preprint server for health sciences · 2024Article
- Biological resilience in health and disease.Disease models & mechanisms · 2024Review
- Attention-deficit/hyperactivity disorder.Nature reviews. Disease primers · 2024Review
- The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Review
- Polygenic resilience score may be sensitive to preclinical Alzheimer's disease changes.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2023Article
Corrections and comments
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Authors and funding
35 authors.
Jiahui HouPsychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA.
Jonathan L HessPsychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA.ORCID 0000-0001-8406-632X
Nicola ArmstrongMathematics and Statistics, Curtin University, Perth, WA, Australia.
Joshua C BisDepartment of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.ORCID 0000-0002-3409-1110
Benjamin Grenier-BoleyU1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, F-59000, Lille, France.
Ida K KarlssonDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Ganna LeonenkoDementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
Katya NumbersCentre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Eleanor K O'BrienCentre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.
Alexey ShadrinNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.ORCID 0000-0002-7467-250X
Anbupalam ThalamuthuCentre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Qiong YangDepartment of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.ORCID 0000-0002-3658-1375
Ole A AndreassenNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.ORCID 0000-0002-4461-3568
Henry BrodatyCentre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0001-9487-6617
Margaret GatzDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.ORCID 0000-0002-1071-9970
Nicole A KochanCentre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Jean-Charles LambertU1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, F-59000, Lille, France.ORCID 0000-0003-0829-7817
Simon M LawsCentre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.ORCID 0000-0002-4355-7082
Colin L MastersThe Florey Institute, The University of Melbourne, Melbourne, VIC, Australia.
Karen A MatherCentre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0003-4143-8941
Nancy L PedersenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Danielle PosthumaDepartment of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, the Netherlands.ORCID 0000-0001-7582-2365
Perminder S SachdevCentre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0002-9595-3220
Julie WilliamsDivision of Psychological Medicine and Clinical Neurology and Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.ORCID 0000-0002-4069-0259
Alzheimer’s Disease Neuroimaging Initiative
Chun Chieh FanDepartment of Cognitive Science, University of California San Diego, La Jolla, CA, USA.ORCID 0000-0001-9437-2128
Stephen V FaraoneDepartment of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
Christine Fennema-NotestineDepartments of Psychiatry and Radiology, University of California San Diego, La Jolla, CA, USA.
Shu-Ju LinDepartment of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Valentina Escott-PriceDementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK.ORCID 0000-0003-1784-5483
Peter HolmansDivision of Psychological Medicine and Clinical Neurology and Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.ORCID 0000-0003-0870-9412
Sudha SeshadriDepartment of Neurology, School of Medicine, Boston University, Boston, MA, USA.
Ming T TsuangDepartment of Psychiatry, University of California San Diego, La Jolla, CA, USA.ORCID 0000-0002-0076-5340
William S KremenDepartment of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Stephen J GlattPsychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, NY, USA. stephen.glatt@psychgenelab.com.ORCID 0000-0002-0360-7567
Funding
The VETSA Longitudinal Twin Study of Cognition and Aging (VETSA 4)R01AG050595 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ELMAN, JEREMY A, FRANZ, CAROL ELAINE · 2015 to 2024
$28.0MCHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5MThe VETSA Longitudinal MRI Twin Study of Aging (VETSA MRI 4)R01AG076838 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ANDERS M DALE, Jeremy A Elman · 2022 to 2026
$8.7MSLE Treatment with N-acetylcysteineU01AR076092 · NIAMS · UPSTATE MEDICAL UNIVERSITY · PI Michael P McDermott, Andras Perl · 2020 to 2026
$7.9MDiscoveries in ADHD genomics: Help or hype in clinical settings?R01MH116037 · NIMH · MASSACHUSETTS GENERAL HOSPITAL · PI DOYLE, ALYSA E · 2019 to 2023
$4.4MGenetic Predictors, Transcriptomic Biomarkers, & Neurobiological Signatures of Resilience to Alzheimer's DiseaseR01AG064955 · NIA · UPSTATE MEDICAL UNIVERSITY · PI FENNEMA-NOTESTINE, CHRISTINE, GLATT, STEPHEN J · 2019 to 2023
$3.8MClarifying risk and protective factors for dementia with the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortiumR01AG060470 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI GATZ, MARGARET, PEDERSEN, NANCY L · 2018 to 2022
$3.6MGene Expression Biomarkers for Early Identification of Mild Cognitive Impairment: A Twin StudyR01AG054002 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLATT, STEPHEN J, TSUANG, MING T. · 2016 to 2019
$2.7MMedical Research Council G0300429Medical Research Council G0902227Medical Research Council MC_PC_17112Medical Research Council MR/K013041/1Medical Research Council MR/L010305/1Medical Research Council MR/L023784/2Medical Research Council MR/L501517/1Medical Research Council MR/T04604X/1NHLBI NIH HHS R01 HL105756NIAMS NIH HHS U01 AR076092NIA NIH HHS R01 AG050595NIA NIH HHS R01 AG054002NIA NIH HHS R01AG054002NIA NIH HHS R01 AG060470NIA NIH HHS R01 AG064955NIA NIH HHS R01AG064955NIA NIH HHS R01 AG076838NIMH NIH HHS R01 MH116037
Abstract
Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer's disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast "resilient" unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.
Indexed as
Alzheimer DiseaseApolipoprotein E4Apolipoproteins EGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMultifactorial InheritanceRisk FactorsApolipoprotein E4Apolipoproteins E
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