Leveraging a Novel Phenotype to Identify Complex Traits and Biological Pathways Associated with Resilience to Alzheimer’s Disease

Abstract Background Previous models of resilience to Alzheimer’s Disease (AD) have relied on cross‐sectional designs and inclusion of measures of neuropathology. Here, we present a novel modeling approach incorporating longitudinal data and the use of APOE and higher order interaction terms to approximate neuropathological resilience, vastly increasing participant diversity and statistical power. We validate this approach and report novel genetic associations with neuropathological resilience. Method Leveraging 20,513 participants (Table 1), we explored the genetics of resilience metrics using mixed‐effects regressions across ancestries. We conducted GWAS on four resilience metrics: two in a “silver” model, which benefit from a larger sample size and did not include neuropathology at autopsy, and two in a “gold” model, which incorporate neuropathology at autopsy. These models were built in all diagnoses and separately in cognitively unimpaired (CU) at baseline participants. Silver‐gold meta‐analyses were conducted to maximize statistical power. Models adjusted for age, sex, APOE ε4 allele count, presence of the APOE ε2 allele and all covariate interactions with interval (years from baseline). Residual cognitive resilience was quantified from residuals in three cognitive domains (memory, executive function, and language). Post‐GWAS analyses included gene and pathway tests using MAGMA and genetic correlation with 65 traits using GNOVA. Result Silver and gold resilience metrics were highly correlated (0.77‐0.88) and showed positive genetic covariance (0.01‐0.13). We identified negative correlations of resilience with multiple sclerosis and neuropsychiatric traits, including Tourette syndrome and schizophrenia (all P FDR <2.6×10 −2 ; Figure 1). Furthermore, we observed three significant pathway associations with resilience: metabolism of amino acids and derivatives in the silver all participants meta‐analysis, negative regulation of transforming growth factor beta production in the silver CU at baseline meta‐analysis, and the SARS pathway in the gold CU at baseline meta‐analysis (all P FDR <5.0×10 −2 ). Finally, we identified a locus on chromosome 17 associated with resilience that approached genome‐wide significance (top SNP: rs757022, MAF = 0.18, b = 0.08, P = 1.1×10 −7 ; Figure 2). Conclusion Using novel, longitudinal modeling approaches, we identified multiple biological pathways and complex traits associated with resilience to AD as well as genetic loci approaching genome‐wide significance. Our findings indicate that silver standard modeling approaches can complement current gold standard methods to accelerate genetic discovery.

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Publication Details

Journal
Alzheimer s & Dementia
Published
2024-12-01
DOI
https://doi.org/10.1002/alz.095693
Primary Topic
Resilience and Mental Health
Type
article
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article

Leveraging a Novel Phenotype to Identify Complex Traits and Biological Pathways Associated with Resilience to Alzheimer’s Disease

Susan M. Resnick, Alan E. Renton, Jared Phillips, Timothy J. Hohman et al.
Alzheimer s & Dementia
Resilience and Mental Health
article

Leveraging a Novel Phenotype to Identify Complex Traits and Biological Pathways Associated with Resilience to Alzheimer’s Disease

Susan M. Resnick, Alan E. Renton, Jared Phillips, Timothy J. Hohman, Emily R. Mahoney, Elizabeth A. Sanders, Sarah Biber, Shannon L. Risacher, Jonathan L. Haines, Julia B. Libby, Michael L. Lee, Emily H. Trittschuh, Edoardo Marcora, Julie A. Schneider, Andrew J. Saykin, Lisa L. Barnes, Keith F. Widaman, Derek B. Archer, Logan C. Dumitrescu, Rachel F. Buckley, C. Dirk Keene, Lori L. Beason‐Held, Li‐San Wang, Lindsay A. Farrer, Michael L. Cuccaro, Carlos C Cruchaga, Shea J. Andrews, Tulsi Patel, Michelle Clifton, Corinne D. Engelman, Paul K. Crane, Michael R. Duggan, Shubhabrata Mukherjee, Walter A. Kukull, Skylar Walters, Angela Lee Jefferson, William S. Bush, Keenan A. Walker, Brandon S. Klinedinst, Phoebe Scollard, Elizabeth C. Mormino, Qiongshi Lu, Brian Fulton‐Howard, Sterling C. Johnson, Michaël E. Belloy, David W. Fardo, Murat Bilgel, Alison Goate, Badri Narayan Vardarajan, Gerard D. Schellenberg, Jesse Mez, Yang An, Lindsay R. Clark, Seo‐Eun Choi, Jason J. Hassenstab, Katherine A. Gifford, Richard Mayeux, Eric B. Larson, Reisa A Sperling, Marilyn S. Albert, David A. Bennett, Margaret A Pericak‐Vance, Alexandra N. Regelson
article en

Abstract

Abstract Background Previous models of resilience to Alzheimer’s Disease (AD) have relied on cross‐sectional designs and inclusion of measures of neuropathology. Here, we present a novel modeling approach incorporating longitudinal data and the use of APOE and higher order interaction terms to approximate neuropathological resilience, vastly increasing participant diversity and statistical power. We validate this approach and report novel genetic associations with neuropathological resilience. Method Leveraging 20,513 participants (Table 1), we explored the genetics of resilience metrics using mixed‐effects regressions across ancestries. We conducted GWAS on four resilience metrics: two in a “silver” model, which benefit from a larger sample size and did not include neuropathology at autopsy, and two in a “gold” model, which incorporate neuropathology at autopsy. These models were built in all diagnoses and separately in cognitively unimpaired (CU) at baseline participants. Silver‐gold meta‐analyses were conducted to maximize statistical power. Models adjusted for age, sex, APOE ε4 allele count, presence of the APOE ε2 allele and all covariate interactions with interval (years from baseline). Residual cognitive resilience was quantified from residuals in three cognitive domains (memory, executive function, and language). Post‐GWAS analyses included gene and pathway tests using MAGMA and genetic correlation with 65 traits using GNOVA. Result Silver and gold resilience metrics were highly correlated (0.77‐0.88) and showed positive genetic covariance (0.01‐0.13). We identified negative correlations of resilience with multiple sclerosis and neuropsychiatric traits, including Tourette syndrome and schizophrenia (all P FDR <2.6×10 −2 ; Figure 1). Furthermore, we observed three significant pathway associations with resilience: metabolism of amino acids and derivatives in the silver all participants meta‐analysis, negative regulation of transforming growth factor beta production in the silver CU at baseline meta‐analysis, and the SARS pathway in the gold CU at baseline meta‐analysis (all P FDR <5.0×10 −2 ). Finally, we identified a locus on chromosome 17 associated with resilience that approached genome‐wide significance (top SNP: rs757022, MAF = 0.18, b = 0.08, P = 1.1×10 −7 ; Figure 2). Conclusion Using novel, longitudinal modeling approaches, we identified multiple biological pathways and complex traits associated with resilience to AD as well as genetic loci approaching genome‐wide significance. Our findings indicate that silver standard modeling approaches can complement current gold standard methods to accelerate genetic discovery.

Alzheimer s & DementiaVol. 20(S8)
University of California, Riverside (US), Boston University (US), Brigham and Women's Hospital (US), Rush University Medical Center (US), National Institutes of Health (US), Allen Institute for Brain Science (US), University of Wisconsin–Madison (US), Harvard University (US), University of Kentucky (US), Johns Hopkins University (US), University of Miami (US), The University of Melbourne (AU), University of California, San Francisco (US), Vanderbilt University (US), University of Washington (US), Washington University in St. Louis (US), Columbia University Irving Medical Center (US), Johns Hopkins Medicine (US), Massachusetts General Hospital (US), VA Puget Sound Health Care System (US), Geriatric Research Education and Clinical Center (US), Dr. John T. Macdonald Foundation (US), National Institute on Aging (US), William S. Middleton Memorial Veterans Hospital (US), Case Western Reserve University (US), University of Pennsylvania (US), Vanderbilt University Medical Center (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
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Resilience and Mental Health
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