Plenary 1: SEARCHING FOR GENES INFLUENCING SUCCESSFUL BRAIN AGING

摘要

Population projections suggest for the first time in humanhistory that there will be more individuals over the age of 65 years than below the age of 14 years by 2050. Indeed, the percentage of Americans over the age of 65 years is expected to increase from 13% in 2010 to over 20% in 2040. Thus, there is considerable interest in delineating the biological mechanisms that influence age-related changes to facilitate successful aging. As the brain appears to play a pivotal role in aging biology, one promising strategy is to define measures of brain structure and function that index concomitant aging outcomes. However, the biological bases of successful brain aging are poorly understood and there is considerable debate whether aging is intrinsically 'programmed' or incidental to cumulative environmental exposure. Yet, genes likely regulate both the developmental program and the robustness to environmental exposure, suggesting a role for genetic variation in brain aging. To establish phenotypes for gene discovery projects focused on brain aging, we utilized a quantitative gene-by-environment interaction analysis, where age is treated as an environmental factor, in a large cohort of randomly selected pedigrees (n = 1,129 subjects, age range 18-83 years). We found a heritable basis for neurocognitive and gray-matter deterioration as a function of age. In contrast, increasing white-matter incoherence with age appears to be non-genetic. Here we present linkage analyses, using phenotypes identified via the gene x age (G x A) interaction approach, to localize chromosomal regions involved in brain again. Results of these analyses suggest novel quantitative trait loci influencing successful brain aging.