Linking genetic subtypes of Alzheimer's disease to biological and cognitive heterogeneity

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PROJECT SUMMARY/ABSTRACT The long-term goal of the proposed career development award is to provide me with the training necessary to develop an independent research program focused on elucidating the genetic, biological and cognitive heterogeneity of Alzheimer’s disease (AD) risk. An emphasis on the genetics of biological pathways in the proposed project will complement my existing background in cognitive neuroscience and neuroimaging. The training goals are to: 1) gain training in lab management and develop a multi-disciplinary research program to study AD; 2) gain specific expertise in molecular genetics; and 3) receive training in the biological processes that contribute to AD. These training goals are mutually informative and will be achieved through a mix of formal coursework, hands-on methodological training, and informal discussion. The Psychiatry Department at the University of California, San Diego is an ideal environment in which to receive this training due to the strong presence of world-renown researchers, track record of career development, and state-of-the-field research facilities. Standard models of AD propose a characteristic sequence of pathological events that may accurately describe the progression of some, but not all individuals. However, the failure of AD treatment trials suggests that standard models are not complete. Prior studies have identified variability in domains of cognitive impairment, levels and sequence of pathological events, and the topography of atrophy and pathology in the brain. Interestingly, variability in these biological measures appears to correlate with variability in cognitive impairment. These findings provide evidence suggesting that even “typical” AD may comprise multiple disease subtypes, yet it is unclear to what extent they arise from different etiologies requiring different treatments. Genetic risk in complex diseases such as AD can be summarized using polygenic risk scores (PRSs), but these measures only consider risk along a single continuum, which may obscure different sources of genetic risk. The scientific component of the project will seek to identify genetic subtypes using multiple AD PRSs specific to biological pathways. This project will address two key questions: 1) Is the genetic etiology of AD multidimensional, and 2) how does variability in the genetic risk for AD relate to heterogenous biological and cognitive expressions of the disease? The specific aims are to: 1) determine whether there are subtypes of AD genetic risk using pathway-based PRSs; 2) test whether biological subtypes of AD are associated with different forms of AD genetic risk; and 3) examine whether cognitive impairment subtypes are associated with different forms of AD genetic risk. The project will focus on 4 large-scale studies with multiple biological, cognitive, and genetic measures: Alzheimer’s Disease Neuroimaging Initiative, Baltimore Longitudinal Study of Aging, Vietnam Era Twin Study of Aging, and UK Biobank. Characterizing the variability of disease etiology will inform efforts to develop targeted intervention strategies relevant for disease subtypes. It will also allow more accurate groupings of individuals by subtype to improve sensitivity in detecting disease and therapeutic effects.