Genetic and Environmental Drivers of Cognitive Resilience in Aging Populations - PROJECT SUMMARY/ABSTRACT Alzheimer's disease and related dementias (ADRD) are major sources of health, social, and economic burden. The lack of effective ADRD therapies or strategies to prevent or stop ADRD progression presents a significant public health challenge in the context of aging populations. A focus on resilience, instead of disease, may provide insight into novel treatment and prevention modalities. Cognitively resilient individuals typically retain normal cognitive function despite advanced age or brain pathology. The genetic architectures of cognitive resilience and Alzheimer's disease appear distinct based on recent genomic work. However, further interrogation of the biologic basis of cognitive resilience, including the interplay between genetic and environmental factors, is necessary to design targeted interventions that build cognitive resilience in older adults. We posit that a multi-omics approach can identify novel cognitive resilience loci and elucidate pathways that promote cognitive resilience and lower the risk of ADRD. We propose to use extant genomic data, high- quality longitudinal measurements of 5,000 plasma proteins, repeat psychometric assessments, and neuroimaging in the Atherosclerosis Risk in Communities (ARIC) study to accomplish the following specific aims: (1) employ a multi-omic approach to identify causal loci and biomarkers for cognitive resilience in community-dwelling older adults and (2) decompose the genetic and environmental drivers of cognitive resilience. In Aim 1, we will conduct a proteome-wide association study (PWAS) to identify proteins associated with cognitive resilience. Given heterogeneity in the measure of cognitive resilience in epidemiologic studies, we will use psychometric and imaging-based definitions of cognitive resilience. We will also identify protein quantitative trait loci, perform fine-mapping, and use Mendelian Randomization to identify causal markers of cognitive resilience. In Aim 2, we will build and validate a polygenic risk score (PRS) for cognitive resilience. The PRS will be applied to model the interplay of genetic and modifiable environmental factors on cognitive resilience. This award will support my transition to aging research and my immediate and long-term goals through (1) advanced training in molecular, neuro-, and aging epidemiology and (2) the mentored application of these methods in an innovative research question aligned with priorities in population aging research. With the dedication of a highly qualified and enthusiastic team of mentors, the successful completion of these aims will deepen the field's understanding of the determinants of cognitive resilience. Further, the training objectives nested in the F99 and K00 phases of this award will prepare me for a career in which I will lead an interdisciplinary team as an independent investigator in aging research
