Genetic variants and functional pathways associated with resilience to Alzheimer's disease

Logan Dumitrescu, Emily R. Mahoney, Shubhabrata Mukherjee, Michael L. Lee, William S. Bush, Corinne D. Engelman, Qiongshi Lu, David W. Fardo, Emily H. Trittschuh, Jesse Mez, Catherine Kaczorowski, Hector Hernandez Saucedo, Keith F. Widaman, Rachel Buckley, Michael Properzi, Elizabeth Mormino, Hyun Sik Yang, Tessa Harrison, Trey Hedden, Kwangsik NhoShea J. Andrews, Doug Tommet, Niran Hadad, R. Elizabeth Sanders, Douglas M. Ruderfer, Katherine A. Gifford, Annah M. Moore, Francis Cambronero, Xiaoyuan Zhong, Neha S. Raghavan, Badri Vardarajan, Margaret A. Pericak-Vance, Lindsay A. Farrer, Li San Wang, Carlos Cruchaga, Gerard Schellenberg, Nancy J. Cox, Jonathan L. Haines, C. Dirk Keene, Andrew J. Saykin, Eric B. Larson, Reisa A. Sperling, Richard Mayeux, David A. Bennett, Julie A. Schneider, Paul K. Crane, Angela L. Jefferson, Timothy J. Hohman

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values 5 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values 5 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values 4 0.42) nor associated with APOE (P-values 4 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

Original languageEnglish
Pages (from-to)2561-2575
Number of pages15
Issue number8
StatePublished - Aug 1 2020

Bibliographical note

Funding Information:
The results published here are in part based on data obtained from the AMP-AD Knowledge Portal (doi:10.7303/ syn2580853). MSBB data were generated from post-mortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr Eric Schadt from Mount Sinai School of Medicine. MayoRNAseq data were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr Nilufer Ertekin-Taner and Dr Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30-AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research. Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd and NIH grants R01-MH085542, R01-MH093725, P50-MH066392, P50-MH080405, R01-MH097276, RO1-MH075916, P50-M096891, P50-MH084053S1, R37-MH057881, AG02219, AG05138, MH06692, R01-MH110921, R01-MH109677, R01-MH109897, U01-MH103392, and contract HHSN271201300031C through IRP NIMH. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer's Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories, and the NIMH Human Brain Collection Core. CMC Leadership: Panos Roussos, Joseph Buxbaum, Andrew Chess, Schahram Akbarian, Vahram Haroutunian (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Enrico Domenici (University of Trento), Mette A. Peters, Solveig Sieberts (Sage Bionetworks), Thomas Lehner, Stefano Marenco, Barbara K. Lipska (NIMH). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen Inc Cambridge, MA 02139, provided support for genotyping of the A4 Study cohort; Bristol-Myers Squibb Company; CereSpir, Inc; Cogstate; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The Alzheimer's Disease Genetics Consortium supported genotyping, and data processing of samples through National Institute on Aging (NIA) grants U01-AG032984. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01). Additional data collection and sharing for this project was funded by the Alzheimer's Disease Metabolomics Consortium (National Institute on Aging R01-AG046171, RF1-AG051550 and 3U01-AG024904-09S4). This research was supported in part by K01-AG049164, R01-AG059716, R21-AG05994, K12-HD043483, K24-AG046373, HHSN311201600276P, S10-OD023680, R01-AG034962, R01-NS100980, R01-AG056534, P30-AG010161, R01-AG057914, R01-AG15819, R01-AG17917, R13-AG030995, U01-AG061356, U01-AG006781, K99-AG061238, U01-AG46152, Howard Hughes Medical Institute James H. Gilliam Fellowship for Advanced Study (FEC), F31-AG059345 (FEC), UL1-TR000445 and the Vanderbilt Memory & Alzheimer's Center. Data collection was supported through funding by NIA grants P50-AG016574, P50-AG005136, R01-AG032990, U01-AG046139, R01-AG018023, U01-AG006576, U01-AG006786, R01-AG025711, R01-AG017216, R01-AG003949, P30-AG19610, U01-AG024904, U01-AG032984, U24-AG041689, R01-AG046171, RF1-AG051550, 3U01-AG024904-09S4, NINDS grant R01-NS080820, CurePSP Foundation, and support from Mayo Foundation.

Publisher Copyright:
© The Author(s) (2020).


  • Alzheimer's disease
  • Amyloid
  • GWAS
  • Reserve
  • Resilience

ASJC Scopus subject areas

  • Medicine (all)


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