The goal of the current study is to investigate how individual differences in health status and genetic risk for cognitive impairment affect the regional distribution and severity of brain changes associated with aging and age-related cognitive decline. Previous studies have shown that the frontal cortex is preferentially affected in aging and is important for cognitive abilities that often decline with age, including working memory, attention, and executive functions. Several health and genetic risk factors have been specifically associated with declines in cognition and brain abnormalities in regions of the temporal, parietal, cingulate, and frontal cortices and white matter in otherwise neurologically healthy elderly. Among these factors include differences in blood pressure, aerobic fitness, and the presence of the apolipoprotein E (APOE) s4 allele, a common susceptibility gene for Alzheimer's disease. Health and genetic risks factors may interact with the effects of aging to account for the heterogeneity of cognitive decline and atrophic brain regions commonly observed among active elderly, living in the community. We plan to study 222 community dwelling, neurologically healthy elderly with baseline tests of ambulatory blood pressure and aerobic fitness, baseline and two year follow-up structural and diffusion tensor magnetic resonance imaging (MRI) scans, APOE genotyping, and baseline and two year follow up assessments of cognitive function using a battery of standardized neuropsychological tests. We will test hypotheses using regional univariate and multivariate network analysis methods with voxel-based MRI morphometry to identify the baseline and two year longitudinal changes in gray and white matter associated with aging;to determine how age interacts with three potentially modifying factors: a) blood pressure, b) aerobic fitness, and c) APOE genotype to alter the regional distribution and severity of baseline and two year longitudinal gray and white matter changes in aging;and to evaluate how specific brain regions identified by the interactive effects of aging with health status and genetic risk for cognitive impairment are associated with baseline and two year declines in cognition. It is expected that results from this study will significantly enhance our understanding of the brain changes associated with aging and related cognitive decline, help to identify those at greatest risk for age- related cognitive dysfunction, and provide a foundation to develop and test focused strategies to delay or prevent the brain changes that lead to cognitive decline in aging.
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