PROJECT SUMMARY/ABSTRACT This K23 proposal will investigate the timing of the relationship between vascular risk and amyloid (Aβ) on tau accumulation during the preclinical stages of Alzheimer’s disease (AD), to determine the critical window for intervention. Our prior studies demonstrated a synergy between specific vascular risks, especially high systolic blood pressure (SBP) and body mass index (BMI), with Aβ in accelerating tau PET burden and cognitive decline in preclinical AD. The prevalence and modifiability of hypertension and obesity add to their excellent potential as combination therapeutic targets with Aβ for prevention efforts in AD. However, the optimal age group to target for intervention remains unknown. Epidemiology studies suggest that midlife vascular risks are most strongly associated with increased risk of AD, while effects are mixed or reversed in late-life. The goal of this project is to address the following key knowledge gaps: 1) how early and over what age period do elevated SBP and BMI, synergistically with Aβ accumulation, drive greater tau pathology, 2) whether plasma phosphorylated tau (p-tau) measures may be more sensitive than tau PET in detecting an early interaction in midlife when the AD pathological burden is low, and 3) how longitudinal changes of these tau measures relate to the synergistic effects of vascular risk and Aβ on prospective cognitive decline. We will accomplish these goals using an innovative approach: i) harmonizing the breadth of cross-sectional data from the Harvard Aging Brain Study (HABS) and Framingham Heart Study across 5+ decades from mid- to late-life to determine the timing of the vascular-Aβ effects on tau PET (Aim 1) and plasma p-tau (Aim 2), and ii) leveraging the depth of longitudinal characterization in HABS to elucidate the effects on longitudinal tau pathology, and determine how changes in tau PET and p-tau relate to cognitive decline (Aim 3). Our findings will inform the design of combination clinical trials targeting vascular risk and Aβ in preclinical AD, by identifying the population at risk and by establishing whether plasma p-tau can detect this early synergy, which can greatly expand accessibility and diversity of research studies. Our preliminary results suggest that the synergistic effects on tau pathology are greatest during midlife, which has the potential to shift research and clinical practice paradigms to focus prevention efforts even earlier. This career development award will be powered by a cohesive mentorship and advisory team of leading experts with complementary expertise in AD and vascular contribution to cognitive impairment and dementia (VCID). The rigorous training plan will enable the candidate – a practicing cognitive neurologist with a strong commitment to AD research, to acquire new expertise in PET methodologies, plasma biomarkers, epidemiology and mechanisms of VCID, and advanced statistical methods including clinical trials design. The scientific kno...