Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups

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30 Scopus citations

Abstract

Categorizing people with late-onset Alzheimer’s disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer’s disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10−5 and odds ratios more extreme than those previously reported for Alzheimer’s disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10−27). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10−5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.

Original languageEnglish
Pages (from-to)2942-2951
Number of pages10
JournalMolecular Psychiatry
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Funding Information:
Acknowledgements Analyses were funded by R01 AG042437 (PKC, PI) and R01 AG029672 (PKC, PI). Data archiving was supported by R01 AG042437-S1 (PKC, PI). JM’s efforts were also supported by K23 AG046377 (JM, PI). The efforts of LEG, TJG, and CDK were also supported by P50 AG005136 (TJG, PI). CDK’s efforts were also supported by the Nancy and Buster Alvord Endowment. ALG’s efforts were supported by K01 AG050699 (ALG, PI). TDB’s efforts were supported by Department of Veterans Affairs Research Funds. AJS’s efforts were supported by U01 AG042904 (Weiner M, PI), P30 AG010133 (AJS, PI), and R01 AG019771 (AJS, PI). ACT data collection was supported by U01 AG006781 (Larson E and Crane P, MPIs). ACT genotyping was supported by U01 HG006375 (EBL and G. Jarvik, MPIs). Cerebellum samples for genotyping for some ACT samples were prepared with support from P50 AG005136 (TJG, PI). The authors thank Aimee Schantz and Allison Beller for administrative support for the ACT cerebellum samples. ADNI data collection and genotyping were supported by U01 AG024904 (Weiner M, PI). 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; 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 (www.fnih.org). 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. MAP data collection and genotyping were supported by R01 AG017917 (DAB, PI). Additional genotyping was supported by Kronos, Zinfandel, and U01 AG032984 (Schellenberg G, PI). ROS data collection and genotyping were supported by P30 AG10161 (DAB, PI), R01 AG15819 (DAB, PI), and R01 AG30146 (D. Evans, PI). Additional genotyping was supported by Kronos, Zinfandel, and U01 AG032984 (G. Schellenberg, PI). PITT data collection were funded by P50 AG05133 (OLL, PI), R01 AG030653 (MIK, PI), and R01 AG041718 (MIK, PI).

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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