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.neurocognition | diffusion tensor imaging | fractional anisotropy | genetic correlation | gene x environment interaction P opulation projections suggest for the first time in human history there will be more individuals over the age of 65 than below the age of 14 by 2050 (1). This milestone reflects the dramatic increase of the average lifespan of people worldwide, rather than a reduction in the total number of children being born. Indeed, 25% of the US population is expected to be over the age of 60 midway through this century (1). The implications of our aging population are substantial, because aging is associated with decreased mental and physical ability coupled with increased health care utilization. Thus, there is considerable interest in delineating the biological mechanisms that influence age-related changes to facilitate successful aging (2), defined as avoidance of disease or disability, maintaining good physical and cognitive function, and engagement in social and productive activities. Because the brain appears to play a pivotal role in aging biology (3), one promising strategy is to define measures of brain structure and function that index concomitant aging outcomes (4). The observation that many measures of brain aging are heritable and can be localized to specific genomic regions (6) indicates that genetic factors play a crucial role in the brain's ability to either prosper or ...

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