OVERALL – PROJECT SUMMARY/ABSTRACT This is a continuing multi-disciplinary program on VASCULAR CONTRIBUTIONS TO DEMENTIA AND GENETIC RISK FACTORS FOR ALZHEIMER’S DISEASE with multiple projects, cores, institutions and 24 investigators from the Zilkha Neurogenetic Institute, Stevens Neuroimaging and Informatics Institute, Alzheimer’s Disease Research Center (ADRC), University of Southern California (USC), LA, CA; Washington University Knight ADRC, Dept. of Neurology, Washington University, St. Louis, MO; Huntington Medical Research Institutes, Pasadena, CA; Banner Alzheimer’s Institute and Mayo Clinic, AZ; Dept. of Psychology, UC Irvine; Dept. of Molecular Medicine, Scripps Research Institute ; and Centre for Clinical Brain Sciences, Univ. of Edinburgh, Scotland. The overall goal of the program is to test the ‘neurovascular hypothesis’ of AD and establish whether the neurovasculature has a major role in the pathogenesis of early cognitive decline, and therefore could be a key new therapeutic target to treat early cognitive impairment, dementia and early AD. The program includes continuing participation by accomplished investigators in all aspects of this research plan. The collective expertise of the investigators, overall environment, preliminary results, and experimental design for each of the projects and supporting cores produced considerable success of this program over the past 4 years. During this period we collected vast amounts of data, analyzed them and wrote an impressive number of high impact papers. Our renewal is concentrated on apolipoprotein E (APOE), the major genetic risk factor for AD. We propose longitudinal studies in APOE4 carriers (ε3/ε4; ε4/ε4) that are at high genetic risk for AD and develop early cerebrovascular changes including breakdown in the blood-brain barrier (BBB) relative to APOE3 homozygotes (ε3/ε3) that are at a lower risk for AD and develop slower cerebrovascular changes. We anticipate following 402 APOE4 carriers and 465 APOE3 homozygotes (ages 45-90) initially enrolled as cognitively unimpaired (CU, 75%) or with mild cognitive impairment (MCI, 25%). This includes 510 participants enrolled in the program during the initial P01 period, and 360 new participants to be recruited during the first 3 years of the renewal. In these APOE4 and APOE3 participants we will apply cutting-edge molecular and imaging methods to study the contribution of BBB/vascular dysfunction to preclinical cognitive decline, loss of brain connectivity, neurodegeneration, and longitudinal clinical progression along the continuum from CU to MCI, and MCI to dementia, in relation to Aβ and tau AD biomarker abnormalities (CSF, PET). Experimentally, we will study how BBB/vascular dysfunction relates to synaptic and neuronal dysfunction and behavior in APOE (knock-in)flox/flox (KIF) mice with and without apoE deletion from astrocytes and pericytes (key sources of BBB-associated apoE), and in these mice crossed with APP/PS1-21 and P301S tau lines, and treated with a cell-signaling activated protein C (APC) analog, 3K3A-APC. The results of this work may lead to new ways of thinking about pathogenesis, treatment and early prevention of cognitive impairment, dementia and AD for which we still do not have effective therapies.

OVERALL NARRATIVE This is a continuing multi-disciplinary program on VASCULAR CONTRIBUTIONS TO DEMENTIA AND GENETIC RISK FACTORS FOR ALZHEIMER’S DISEASE with multiple projects, cores, institutions and investigators. The overall goal of the program is to test the ‘neurovascular hypothesis’ of AD and establish whether the neurovasculature has a major role in the pathogenesis of early cognitive decline, and therefore could be a key new therapeutic target to treat early cognitive impairment, dementia and early AD. The results of this work may lead to new ways of thinking about pathogenesis, treatment and early prevention of cognitive impairment, dementia and AD for which we still do not have effective therapies.