The VETSA Longitudinal MRI Twin Study of Aging (VETSA MRI 4)

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PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is costly and burdensome. As the US population ages, AD’s public health impact continues to grow. NIH and Alzheimer’s Association consensus statements indicate that understanding early phases of disease progression—such as mild cognitive impairment (MCI)—beginning in middle age is key to slowing dementia onset. Identifying at-risk individuals early is also estimated to result in massive savings. Despite the protracted progression of AD brain pathology, little is known about its temporal course from middle to older age, particularly for neuroimaging indices. The Vietnam Era Twin Study of Aging (VETSA) focuses on early identification of risk for MCI/AD and AD-related brain changes beginning when subjects were in their 50s. The proposed VETSA MRI wave 4 project, with a mean age of 74 (67-78), occurs during a time of increased incident MCI/AD. That, in combination with our longitudinal data, allows for improved ability to determine neuroimaging correlates, trajectories, and their predictors. Continued data collection will allow us to examine the transition period from pre- to post-disease onset and expand on prediction from midlife for an increasing number of individuals. This project is linked to the funded general VETSA 4 grant (AG050595) which collects 10-12 hours per subject of cognitive, health/medical, psychosocial and biomarker data. In addition, we can elucidate genetic and environmental influences on these processes via combined twin and genome-wide genotyping/polygenic score data. We also capitalize on early (age 20) cognitive data, a unique feature enabling us to differentiate cognitive decline from longstanding differences. We request funds to cover MRI acquisition, processing, and analysis (n=500), leveraging associated ongoing work in the general VETSA 4 grant. Aims are: 1) Develop, validate, and characterize novel early brain indicators of risk for MCI/AD. We will develop and validate a novel AD brain signature based on diffusion MRI and show that this brain signature of adults who are only in their 50s improves prediction of progression to MCI. We also hypothesize that integrity of the locus coeruleus—the earliest brain site of tau deposition—will be another early, sensitive risk indicator. 2) Examine cerebrovascular risk factors and their relationship with cognition and AD biomarkers. Cerebrovascular disease (CVD) is the most common pathology concomitant with AD and may contribute to disease progression or be an independent source of brain and cognitive decline. We particularly focus on CVD markers of white matter hyperintensities and arterial spin labeling (ASL) perfusion. 3) Quantify the magnitude of neurodegeneration from midlife to early old age and its underlying genetic and environmental influences. We will examine genetic influences on longitudinal change in macro- and micro-structural brain measures. Our approach includes identifying mediating/moderating effects of risk factors across the lifespan and leveraging our twin and genome-wide genotype data. Covering ~18 years, this project will be a resource for advancing knowledge about early identification of risk for MCI/AD, with potential for a profound public health impact.