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

Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):19006-11. doi: 10.1073/pnas.1313735110. Epub 2013 Nov 4.

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.

Keywords: diffusion tensor imaging; fractional anisotropy; gene x environment interaction; genetic correlation; neurocognition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Aging / genetics
  • Aging / physiology*
  • Analysis of Variance
  • Anisotropy
  • Brain / pathology
  • Brain / physiology*
  • Cognition / physiology*
  • Diffusion Tensor Imaging
  • Humans
  • Memory Disorders / genetics
  • Memory Disorders / physiopathology*
  • Mexican Americans / genetics*
  • Middle Aged
  • Nerve Fibers, Myelinated / pathology
  • Nerve Fibers, Myelinated / physiology*
  • Neuroimaging
  • Pedigree