Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to Alzheimer’s disease associated viruses

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Alzheimer’s is an incurable disease characterized by progressive accumulation of amyloid and tau neuropathology along with neurodegeneration. We do not fully understand the full spectrum of molecular pathways contributing to disease etiology in disease resident central nervous system tissue, specifically as a function of the temporal phases of disease. Furthermore, while genetic association studies have identified a myriad of loci associated with AD risk, it is still unclear how these risk factors modify risk for AD via cellular specific pathways at specific temporal phases of disease. Finally, there is increasing evidence for heterogeneity of disease presentation, including sex heterogeneity as well as neuropathological heterogeneity (e.g. amyloid, tau, TDP-43, Lewy bodies, alpha-synucleinopathy, cerebral amyloid angiopathy), suggesting there may be distinct molecular mechanisms driving disease among subsets of patients. To address these complexities we propose this administrative supplement to leverage the rich multi-omic data available in the AMP-AD consortium address to construct temporal models of AD progression. Such models will form a conceptual framework to enable the interpretation of diverse molecular data and provide a principled means to contextualize peripheral immunological and biomarker data for further study.