Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging

David V. Glahn, Jack W. Kent, Emma Sprooten, Vincent P. Diego, Anderson M. Winkler, Joanne E Curran, D. Reese McKay, Emma E. Knowles, Melanie A Carless, Harald HH Goring, Thomas D. Dyer, Rene L. Olvera, Peter T. Fox, Laura A Almasy, Jac Charlesworth, Peter Kochunov, Ravindranath Duggirala, John C Blangero

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Identification of genes associated with brain aging should markedly improve our understanding of the biological processes that govern normal age-related decline. However, challenges to identifying genes that facilitate successful brain aging are considerable, including a lack of established phenotypes and difficulties in modeling the effects of aging per se, rather than genes that influence the underlying trait. In a large cohort of randomly selected pedigrees (n = 1,129 subjects), we documented profound aging effects from young adulthood to old age (18-83 y) on neurocognitive ability and diffusion-based white-matter measures. Despite significant phenotypic correlation between white-matter integrity and tests of processing speed, working memory, declarative memory, and intelligence, no evidence for pleiotropy between these classes of phenotypes was observed. Applying an advanced quantitative gene-by-environment interaction analysis where age is treated as an environmental factor, we demonstrate a heritable basis for neurocognitive deterioration as a function of age. Furthermore, by decomposing gene-by-aging (G × A) interactions, we infer that different genes influence some neurocognitive traits as a function of age, whereas other neurocognitive traits are influenced by the same genes, but to differential levels, from young adulthood to old age. In contrast, increasing white-matter incoherence with age appears to be nongenetic. These results clearly demonstrate that traits sensitive to the genetic influences on brain aging can be identified, a critical first step in delineating the biological mechanisms of successful aging.

Original languageEnglish (US)
Pages (from-to)19006-19011
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number47
StatePublished - Nov 19 2013

ASJC Scopus subject areas

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