A genome-wide scan for common variants affecting the rate of age-related cognitive decline

Philip L. De Jager, Joshua M. Shulman, Lori B. Chibnik, Brendan T. Keenan, Towfique Raj, Robert S. Wilson, Lei Yu, Sue E. Leurgans, Dong Tran, Cristin Aubin, Christopher D. Anderson, Alessandro Biffi, Jason J. Corneveaux, Matthew J. Huentelman, Jonathan Rosand, Mark J. Daly, Amanda J. Myers, Eric M. Reiman, David A. Bennett, Denis A. Evans

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (PDISC = 5.6 × 10-9; PJOINT = 3.7 × 10-27). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (PDISC = 6.7 × 10-5; PREP = 9.4 × 10-3; PJOINT = 2.3 × 10-5). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.

Original languageEnglish
Pages (from-to)1017.e1-1017.e15
JournalNeurobiology of Aging
Issue number5
StatePublished - May 2012
Externally publishedYes


  • Alzheimer's disease
  • Cognitive decline
  • Genetic risk score
  • Genome-wide association study


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