The Problem: Dementia is usually a multi-factorial process wherein multiple, co-existing brain pathologies result in progressive cognitive impairment. Cerebrovascular disease (CVD) is common among cognitively impaired individuals and has a significant impact on cognition. In addition, there is no clear understanding of how AD and CVD pathologies co-evolve and possibly interact. Due to these two issues, intervention trials on different dementia populations may produce different results due to the differences in CVD burden.

Overall Approach: We will follow these four broad steps to enable the inclusion of required CVD information in clinical trials: i) develop novel multi-band diffusion tensor imaging (DTI)-based metrics that capture prodromal cerebrovascular health-related brain changes; ii) summarize the primary CVD-related changes (based on MRI) into three broad novel mechanistic categories of small vessel disease (SVD) related to hypertensive arteriopathy or SVD-H, cerebral amyloid angiopathy or SVD-CAA, and large artery/embolic disease (LVD), iii) investigate the effect of DTI, SVD-H, SVD-CAA, and LVD on cognition and AD biomarker trajectories in individuals with AD pathologic change[amyloid positive (A+) and amyloid & tau positive (A+T+)], and iv) finally, determine the minimal set of CVD features that are important to include in clinical trials.

Why Mayo Clinic Study of Aging? The population-based nature of the Mayo Clinic Study of Aging (MCSA) sample is ideally suited for this proposal and for generalizability of study findings. Population-based recruitment mechanism in MCSA enables the inclusion of individuals that span range of CVD needed to tease out true associations. Study designs, such as ADNI where the recruitment criterion requires the exclusion of individuals with greater vascular risk, do not lend themselves to investigating the interactions between CVD and AD trajectories. In addition to the generalizable population, the investigators in the MCSA have a broad spectrum of clinical and imaging expertise.