. Efforts to improve treatment of Alzheimer?s disease (AD) are beginning to focus on early identification because diagnosing individuals in the mild cognitive impairment (MCI) stage could improve patient quality of life and substantially reduce the financial impact of the disease. Cognitive assessments in middle age provide ideal early predictors or screeners because they are low cost and non- invasive tools. Although predictive studies of MCI and AD generally focus on episodic memory, executive functions (EFs) are of substantial importance because they control and integrate multiple cognitive processes, and because their performance and associated brain regions are some of the first to decline in middle age. Indeed, there are prominent deficits in EFs in MCI and AD, but few studies have examined these associations longitudinally. We propose that EF deficits can appear as early (or earlier) than memory deficits in the progression to MCI and AD. We will evaluate EFs and memory as predictors of MCI in middle age in combination with another promising early indicator ? AD polygenic scores (Aim 1). Genetic risk scores may become highly useful in prospective studies because genotyping procedures are also non-invasive and can be done anytime in life. Specifically, we will examine whether cognitive measures predict MCI more strongly in individuals with high AD genetic risk scores. We will also examine how other early life factors (cognitive reserve) elucidate the associations between EFs, white matter, and AD genetic risk in midlife (Aim 2). We will examine data from the Vietnam Era Twin Study of Aging, which follows a large sample of male twins across 3 time-points in late middle age (mean age 56, 62, and 67; N~1200 at each wave). Twins completed extensive assessment of EFs at all waves (including multiple measures of response inhibition, task-set shifting, working memory, and verbal fluency) as well as multiple measures of other cognitive abilities (including memory), health, and cardiovascular factors. Early adult general cognitive ability (N=1552; our proxy for cognitive reserve) and genotyping (N=1162) are available for most individuals. White matter data are also available for many subjects (N~ 350 to 400 at each wave). The comprehensive cognitive assessment in VETSA allows for the examination of EFs and memory at the level of latent variables, increasing power and generalizability of findings. Moreover, the genetically-informative nature of the sample (i.e., twins and direct genotyping), allows for the decomposition of associations between EFs and white matter into genetic and environmental influences, and examination of the role of AD genetic risk scores in these associations. This award will provide an ideal opportunity to advance our understanding of EFs and cognitive changes across middle age in a rich dataset. Because all research involves secondary analyses of existing data, there will be ample time to achieve the research aims of this proposal. This work will also lead to the development of independently funded projects (e.g., R01) aimed at improving early identification of MCI and AD risk.
The goal of the project is to elucidate the role of executive functions as risk factors for progression to mild cognitive impairment and brain aging. Executive functions include complex cognitive control processes that are crucial for everyday functioning and interlinked with dementia, psychopathology, and neurodegenerative problems, but they are drastically understudied compared to episodic memory in relation to risk for mild cognitive impairment and Alzheimer?s disease. Understanding how executive function tests aid in prediction of progression to mild cognitive impairment and white matter hyperintensities (in combination with other genetic, cognitive, and biological risk factors) will be crucial to our understanding of early Alzheimer?s disease risk, including future disease prevention, identification, and treatment efforts.
