Project-1 Summary/Abstract: Our group has been testing the hypothesis that systemic and cerebral vascular diseases are risk factors for Alzheimer's disease (AD), and that vascular disease modulates the onset of the cognitive syndrome. That is, there is a vascular-related vulnerability state that alters brain structure and regional blood flow, which interferes with the brain's ability to compensate for the development of the AD pathology, and thus reducing the clinical latency period for the onset of MCI and later clinical AD. However, in the process of testing this hypothesis, we have found that there is close relationship between Aβ deposition and vascular disease, and that the pathological events leading to clinical dementia may be more complex and heterogeneous than previously thought. These new findings indicate that vascular disease has a double role in the pathophysiology of AD; as a factor that alters brain structure and as a contributor to Aβ deposition. We believe that is essential to compare and contrast the relative merits of two hypotheses: 1) vascular disease, Aβ deposition and neurodegeneration are independent predictors of dementia, and increased vascular disease increases the risk of earlier manifestation of cognitive symptoms by increasing a vulnerability state and interfering with vascular-related compensatory mechanisms, and 2) vascular disease accelerates the Aβ deposition, and consequently, this interaction accelerates the onset of clinical symptoms. While there are subtle differences between them, the implications of the two are critically different, and this can affect our understanding of the pathophysiology of dementia in old age, and by extension, its preventive treatments. In order to achieve the study aims, we will complete the follow-up of 191 individuals at high risk for AD (age 85+) who were followed with detailed annual clinical evaluations since 2000, had C11 Pittsburgh compound B (PiB) PET and brain MRI studies, and measures of inflammatory markers in 2009, and structural and perfusion MRI and PiB PET, and vascular studies between 2010-11 and 2015. In this proposal, we will complete annual neuropsychological and neurological exams on all participants, repeat structural and arterial spin-labeled MRI, and PiB PET scans to identify abnormalities in CNS structure, function and Aβ deposition, repeat carotid Doppler, EKG, and measures of arterial stiffness to determine severity of systemic sub-clinical vascular disease, determine the levels of inflammatory markers, and perform tau ligand scans using [F-18]AV-1451 PET to determine severity of tau protein deposition. At the end of the proposed study, we will have two decades of data, which include clinical evaluations, laboratory tests, incidence and prevalence of clinical and subclinical cardiovascular disease. This provides us with a unique opportunity to examine the pathological mechanisms that lead to abnormal cognition in the elderly.