PROJECT SUMMARY Chronic, systemic inflammation is an established mediator of cognitive decline and Alzheimer’s disease (AD) and Alzheimer’s disease-related dementias (ADRD) in older adults. Large-scale genetic studies have strengthened evidence that inflammatory genes play a major role in neuroinflammation that leads to neurodegeneration and cognitive loss. Dietary omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (from fish, nuts, seeds, and certain oils) can be anti-inflammatory. However, evidence of anti-inflammatory and cognitive protection from dietary fatty acids is mixed, even in randomized, controlled interventions. Genetic variants that affect systemic inflammation likely contribute to inconsistent associations between n-3 and n-6 fatty acids and cognitive function. To investigate this hypothesis, we will conduct genome-wide interaction analyses of common variants with linoleic acid (18:2, n-6), arachidonic acid (20:4, n-6), alpha-linolenic acid (18:3, n-3), eicosapentaenoic acid (20:5, n-3), docosahexaenoic acid (22:6, n-3) for the outcomes of high- sensitivity C reactive protein (CRP) and interleukin 6 (IL-6) in multi-ethnic cohorts (Hispanic and African Americans, Chinese and European descent) and combine them meta-analytically. Next, we will conduct similar interaction analyses with the same five n-3 and n-6 fatty acids and low frequency/rare genetic variants, which are likely to be of larger effect size. Genetic variants that we identity though interaction analyses as predicted to respond to each fatty acid for CRP and IL-6 will then be combined to generate a polygenic risk score for evaluation of association with 1) incident dementia and 2) a harmonized overall cognitive function score in a subset of CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) cohorts with robust cognitive outcomes. Several aspects of our design increase its rigor. First, CHARGE populations are located in the US, Europe and Asia and provide a critical multi-ethnic platform to identify genetic sources of variability in response to fatty acids. The multi-national, multi-ethnic aspect is essential because fatty acids profiles, dietary patterns and genetic architecture differ by ethnicity and across the globe. Second, participating cohorts have already measured a panel of individual, common fatty acids in the blood, providing an objectively assessed biomarker of dietary intake and endogenous metabolism. This blood-based fatty acid measurement is valuable, because it provides a precise measurement of essential dietary fatty acids, to improve gene-diet interaction discovery. This research will provide critical evidence of how five common dietary fatty acids ameliorate the genetic risk of systemic inflammatory biomarkers to reduce dementia. Findings from this multi-cohort, interdisciplinary project will inform the design of multi-site dietary interventions to reduce systemic inflammation, to prevent or delay AD and ADRD.