Role of Impaired Cognitive States and Risk Factors in Conversion to Mixed Dementias

We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively, how to account for reverse transitions, how to distinguish prevalence from incidence, and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer’s Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer’s disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI as well as (2) specific forms of dementia (clinical and neuropathological). This leads to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia, for the purpose of rigorous, statistical, biologically-informed analyses that accentuate longitudinal followup: BRAiNS (University of Kentucky), Nun Study (University of Minnesota), Memory and Aging Project (Washington U), Kuakini Honolulu-Asia Aging Study, Religious Orders Study (ROS, Rush Medical University), and the OHSC ADC (Oregon Health & Science University). The database would be publicly accessible and would serve as a unique ‘mineable’ resource for researchers in the field (beyond data accessible through the NACC). Note that three of these studies are NOT ADC cohorts. Specific Aim 2: To harmonize data collected by these centers and thereby identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and ADLs. Specific Aim 3: To study transitions and associated risk factors (e.g., genetic and medical) using novel statistical methods. Specific Aim 4: To harmonize the neuropathology across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g., microinfarcts, Lewy bodies, hippocampal sclerosis, and mixed pathologies etc) influences movement to and from MCI and dementia in order to advance the field in terms of understanding what may prevent complex diseases in brain aging