title: Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging.
abstract: 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.
authors.affiliation: Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, CT 06106.
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.forename: Emma
authors.initials: E
authors.lastname: Sprooten
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Diego
authors.forename: Anderson M
authors.initials: AM
authors.lastname: Winkler
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.forename: D Reese
authors.initials: DR
authors.lastname: McKay
authors.forename: Emma E
authors.initials: EE
authors.lastname: Knowles
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.forename: Rene L
authors.initials: RL
authors.lastname: Olvera
authors.forename: Peter T
authors.initials: PT
authors.lastname: Fox
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Jac
authors.initials: J
authors.lastname: Charlesworth
authors.forename: Peter
authors.initials: P
authors.lastname: Kochunov
authors.forename: Ravi
authors.initials: R
authors.lastname: Duggirala
authors.forename: John
authors.initials: J
authors.lastname: Blangero
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000704:Analysis of Variance; D016880:Anisotropy; D001921:Brain / Q000473:pathology / Q000502:physiology*; D003071:Cognition / Q000502:physiology*; D056324:Diffusion Tensor Imaging; D006801:Humans; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology*; D017058:Mexican Americans / Q000235:genetics*; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000473:pathology / Q000502:physiology*; D059906:Neuroimaging; D010375:Pedigree
keywords: diffusion tensor imaging; fractional anisotropy; gene x environment interaction; genetic correlation; neurocognition