Project Summary RO1 AG 021055 Co-PIs: C. Kawas and M. Corrada The 90+ Study was initiated January 1, 2003 as a population-based cohort study of oldest-old survivors of the Leisure World Cohort Study (LWCS, enrollment 1981-1985). One of the largest (1800+ participants) and longest (14+ years) studies of oldest-old, The 90+ Study has contributed important findings about Alzheimer's disease (AD), dementia, cognitive decline, frailty, and other challenging outcomes associated with aging. The 90+ Study participants, however, display a wide-ranging spectrum of cognitive abilities and neuropathological changes, with many individuals maintaining excellent cognition well into their tenth and eleventh decade, frequently despite the presence of AD and other neuropathologic changes associated with dementia. In this application, we extend our studies to investigate factors related to cognitive resilience including lifestyle, medical histories, education and APOE. Some of these factors were measured more than 30 years earlier as part of the LWCS study. We also continue our investigations of dementia and cognitive decline, taking advantage of the large number of MRI and amyloid PET images obtained during the current funding period. Our innovative approaches include the addition of tau PET which will enable us to examine newly proposed preclinical AD biomarker guidelines in the oldest-old, who are excluded from ADNI and other studies. Finally, dementia in the oldest-old likely reflects the combined effects of low levels of multiple pathologies many of which cannot be measured in vivo (e.g. hippocampal sclerosis (HS), microinfarcts, TDP-43). With state-of-the-art neuropathological investigations and our large cohort of autopsied individuals, we will quantify these complex pathologies to determine the contribution of low levels of vascular and other neuropathologic changes to the expression of dementia in the oldest-old. Thus, our Specific Aims are: Aim 1. Cognitive Resilience: Factors related to superior cognitive performance for age. In this aim we will identify early (30 years earlier in the LWCS) and late (at age 90+) lifestyle and other factors associated with superior cognitive performance. Hypotheses: Cognitive resilience is related to sleep duration, leisure activities, and a positive attitude 30 years earlier; Cognitive resilience is related to high grey matter volume and low ventricular volume (MRI Brain Health) and relative absence of vascular injury independent of the presence of cerebral amyloid on PET. Aim 2. Cognitive Resilience in the Presence of Pathology: Factors related to superior cognitive performance in the presence of dementia-related changes at autopsy (Brain Pathology Burden) In this aim we will examine early and late factors associated with superior cognitive performance in the presence of dementia-related brain changes at autopsy. Hypotheses: Leisure activities and exercise 30 years earlier and at age 90+, education, APOE?2 and absence of medical co-morbidities are associated with cognitive resilience in the presence of neuropathologic changes. Aim 3. Preclinical AD and Vascular Disease: Neuroimaging Profiles and Risk of Dementia and Cognitive Decline In this aim we will prospectively follow non-demented imaged individuals to estimate incidence of dementia and rates of cognitive decline in relation to MRI and PET imaging profiles. Hypotheses: High grey matter volume and low ventricular volume (MRI Brain Health) will predict cognitive outcomes better than the presence of amyloid on PET (A+) or presence of amyloid, tau, and neurodegeneration (A+T+N+) on MRI and PET scans. High levels of vascular burden will be associated with increased risk of dementia. Aim 4. Low levels of Vascular and Other Neuropathologies and Expression of Dementia: In this aim we will study the effect of multiple low levels of pathology in the expression of dementia. Hypotheses: Low levels of multiple pathologies (e.g. AD, microinfarcts, HS, TDP-43) contribute to unexplained dementia in the oldest-old. The expression of dementia in people with high levels of AD pathology at autopsy, is related to the presence (or absence) of low levels of vascular and non-AD pathologies. Aim 5. Study Completion and Public Access Bringing to closure our landmark study, with this renewal we will recruit into The 90+ Study the final living LWCS participants who will turn 90 years of age and follow to death virtually all original LWCS participants. We will complete ascertainment of all established outcomes in The 90+ Study (dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), frailty, disability, and mortality). Finally, we will make these datasets (The 90+ Study and the LWCS) spanning four decades publically available to the research community.