Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease

Jared M Phillips^{1

2}, Logan C Dumitrescu^{1

3}, Derek B Archer^{1

3}, Alexandra N Regelson¹, Shubhabrata Mukherjee⁴, Michael L Lee⁴, Seo-Eun Choi⁴, Phoebe Scollard⁴, Emily H Trittschuh^{5

6}, Walter A Kukull⁷, Sarah Biber⁷, Jesse Mez⁸, Emily R Mahoney¹, Michelle Clifton¹, Julia B Libby¹, Skylar Walters¹, William S Bush⁹, Corinne D Engelman^{10

11}, Qiongshi Lu^{11

12

13}, David W Fardo^{14

15}, Keith F Widaman¹⁶, Rachel F Buckley^{17

18

19}, Elizabeth C Mormino²⁰, R Elizabeth Sanders⁴, Lindsay R Clark^{11

21}, Katherine A Gifford¹, Badri Vardarajan^{22

23

24}, Michael L Cuccaro^{25

26}, Margaret A Pericak-Vance²⁵, Lindsay A Farrer^{8

27

28}, Li-San Wang²⁹, Gerard D Schellenberg²⁹, Jonathan L Haines⁹, Angela L Jefferson¹, Sterling C Johnson²⁰, Marilyn S Albert³⁰, C Dirk Keene³¹, Andrew J Saykin^{32

33

34}, Shannon L Risacher^{32

33

34}, Eric B Larson^{4

35}, Reisa A Sperling^{17

18}, Richard Mayeux^{22

23}, Alison M Goate^{36

37}, Alan E Renton^{36

37}, Edoardo Marcora^{36

37}, Brian Fulton-Howard^{36

37}, Tulsi Patel^{36

37}, David A Bennett³⁸, Julie A Schneider³⁸, Lisa L Barnes³⁸, Carlos Cruchaga³⁹, Jason Hassenstab⁴⁰, Michael E Belloy⁴⁰, Shea J Andrews⁴¹, Susan M Resnick⁴², Murat Bilgel⁴², Yang An⁴², Lori L Beason-Held⁴², Keenan A Walker⁴², Michael R Duggan⁴², Brandon S Klinedinst⁴, Paul K Crane⁴, Timothy J Hohman^{1

2

3}

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
³ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ Department of Medicine, University of Washington, Seattle, WA 98195, USA.
⁵ Department of Psychiatry and Behavior Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
⁶ VA Puget Sound Health Care System, Geriatric Research Education and Clinical Center, Seattle, WA 98108, USA.
⁷ National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁸ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
⁹ Cleveland Institute for Computational Biology, Department of Population & Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
¹⁰ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
¹¹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI 53726, USA.
¹² Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹³ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹⁴ Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY 40536, USA.
¹⁵ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
¹⁶ Graduate School of Education, University of California at Riverside, Riverside, CA 92521, USA.
¹⁷ Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA.
¹⁸ Center of Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.
¹⁹ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC 3010, Australia.
²⁰ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.
²¹ Geriatric Research and Education Center, William S. Middleton Memorial Veteran's Hospital, Madison, WI 53705, USA.
²² Department of Neurology, Columbia University, New York, NY 10032, USA.
²³ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University, New York, NY 10032, USA.
²⁴ The Institute of Genomic Medicine, Columbia University Medical Center and The New York Presbyterian Hospital, New York, NY 10032, USA.
²⁵ John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL 33136, USA.
²⁶ Dr John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miami, FL 33136, USA.
²⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
²⁸ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA.
²⁹ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
³⁰ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³¹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
³² Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³⁴ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³⁵ Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.
³⁶ Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³⁷ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³⁸ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
³⁹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
⁴⁰ Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
⁴¹ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA 94143, USA.
⁴² Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH, Baltimore, MD 21224, USA.

PMID: 40111762
PMCID: PMC12295682 (available on 2026-03-20)
DOI: 10.1093/brain/awaf106

Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease

Jared M Phillips et al. Brain. 2025.

. 2025 Aug 1;148(8):2714-2729.

doi: 10.1093/brain/awaf106.

Authors

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
³ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ Department of Medicine, University of Washington, Seattle, WA 98195, USA.
⁵ Department of Psychiatry and Behavior Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
⁶ VA Puget Sound Health Care System, Geriatric Research Education and Clinical Center, Seattle, WA 98108, USA.
⁷ National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁸ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
⁹ Cleveland Institute for Computational Biology, Department of Population & Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
¹⁰ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
¹¹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI 53726, USA.
¹² Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹³ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹⁴ Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY 40536, USA.
¹⁵ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
¹⁶ Graduate School of Education, University of California at Riverside, Riverside, CA 92521, USA.
¹⁷ Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA.
¹⁸ Center of Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.
¹⁹ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC 3010, Australia.
²⁰ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.
²¹ Geriatric Research and Education Center, William S. Middleton Memorial Veteran's Hospital, Madison, WI 53705, USA.
²² Department of Neurology, Columbia University, New York, NY 10032, USA.
²³ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University, New York, NY 10032, USA.
²⁴ The Institute of Genomic Medicine, Columbia University Medical Center and The New York Presbyterian Hospital, New York, NY 10032, USA.
²⁵ John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL 33136, USA.
²⁶ Dr John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miami, FL 33136, USA.
²⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
²⁸ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA.
²⁹ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
³⁰ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³¹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
³² Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³⁴ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³⁵ Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.
³⁶ Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³⁷ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³⁸ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
³⁹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
⁴⁰ Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
⁴¹ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA 94143, USA.
⁴² Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH, Baltimore, MD 21224, USA.

PMID: 40111762
PMCID: PMC12295682 (available on 2026-03-20)
DOI: 10.1093/brain/awaf106

Abstract

Up to 30% of older adults meet pathological criteria for a diagnosis of Alzheimer's disease at autopsy yet never show signs of cognitive impairment. Recent work has highlighted genetic drivers of this resilience, or better-than-expected cognitive performance given a level of neuropathology, that allow the aged brain to protect itself from the downstream consequences of amyloid and tau deposition. However, models of resilience have been constrained by reliance on measures of neuropathology, substantially limiting the number of participants available for analysis. We sought to determine whether new approaches using APOE allele status, age and other demographic variables as a proxy for neuropathology could still effectively quantify resilience and uncover novel genetic drivers associated with better-than-expected cognitive performance while vastly expanding sample size and statistical power. Leveraging 20 513 participants from eight well-characterized cohort studies of ageing, we determined the effects of genetic variants on resilience metrics using mixed-effects regressions. The outcome of interest was residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function and language) and built within two frameworks: 'silver' models, which obviate the requirement for neuropathological data (n = 17 241), and 'gold' models, which include post-mortem neuropathological assessments (n = 3272). We then performed cross-ancestry genome-wide association studies (European ancestry, n = 18 269; African ancestry, n = 2244), gene- and pathway-based tests and genetic correlation analyses. All analyses were conducted across all participants and repeated when restricted to those with unimpaired cognition at baseline. Despite different modelling approaches, the silver and gold phenotypes were highly correlated (R = 0.77-0.88) and displayed comparable performance in quantifying better- or worse-than-expected cognition, enabling silver-gold meta-analyses. Genetic correlation analyses highlighted associations of resilience with multiple neuropsychiatric and cardiovascular traits [false discovery rate-corrected P (PFDR) values < 5.0 × 10-2]. In pathway-level tests, we observed three significant associations with resilience: metabolism of amino acids and derivatives (PFDR = 4.1 × 10-2), negative regulation of transforming growth factor beta (TGF-β) production (PFDR = 1.9 × 10-2) and severe acute respiratory syndrome (PFDR = 3.9 × 10-4). Finally, in single-variant analyses, we identified a locus on chromosome 17 approaching genome-wide significance among cognitively unimpaired participants (index single nucleotide polymorphism: rs757022, minor allele frequency = 0.18, β=0.08, P = 1.1 × 10-7). The top variant at this locus (rs757022) was significantly associated with expression of numerous ATP-binding cassette genes in brain. Overall, through validating a novel modelling approach, we demonstrate the utility of silver models of resilience to increase statistical power and participant diversity.

Keywords: cognitive reserve; dementia; functional genomics; genome-wide association study; neurodegeneration.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Conflict of interest statement

T.J.H. sits on the scientific advisory board for Vivid Genomics. The remaining authors report no competing interests.

References

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Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease

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Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease

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Conflict of interest statement

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