Caused by advanced cerebral small vessel disease (CSVD), intracerebral hemorrhage (ICH) leaves survivors with a very high risk of incident vascular cognitive impairment and dementia (VCID). While aggressive blood pressure (BP) reduction can reduce the risk of VCID and recurrent stroke, more than 50% of ICH survivors have BP above target, particularly individuals with adverse social determinants of health (SDOH). The parent study, REACH-ICH (R01NS093870), will fill gaps in our knowledge about the role of SDOH after ICH by identifying SDOH-induced environmental risk factors that impact a) VCID after ICH, b) BP treatment resistance, and c) engagement with a program designed to improve treatment of BP. 700 ICH survivors are currently being enrolled through REACH-ICH at multiple centers, divided among White, Black, Hispanic, and Asian participants. Participants are screened with an extensive battery for SDOH exposures, and are followed longitudinally for BP treatment response, cognitive decline, and recurrent stroke. 607 of the participants will receive genome-wide genotyping under the award. Additional analyses building on the REACH-ICH infrastructure could yield biological mechanisms induced by adverse SDOH environments that could be amenable to therapeutic development, at a fraction of the cost of a standalone study. This proposed project, REACH-EpiVCID, will examine epigenetic mediators between SDOH exposures and adverse cognitive outcomes after ICH, as well as BP treatment resistance. Epigenetic changes have already been identified in association with environmental exposures such as air pollution, and have established associations in cardiovascular disease. We will extend these observations to a cohort heavily enriched for CSVD and with an historically high burden of adverse SDOH exposures. REACH-EpiVCID will a) identify epigenetic changes associated with environmental differences induced by SDOH, b) identify epigenetic changes associated with incident VCID and BP treatment resistance after ICH, and c) combine epigenetic associations with DNA genotypes to perform formal mediation analyses and causal inference testing via Mendelian randomization. Epigenetic changes and the mechanistic pathways they highlight are potentially modifiable by small molecules or by behavioral change, and so putative causal associations mediating the effect of SDOH on VCID will represent highly relevant candidates for development of novel treatments to prevent VCID and improve BP treatment resistance after ICH. Further, because epigenetic mediators between SDOH and VCID are likely to be initiated by adverse environmental exposures, treatment targets arising from this approach stand to have the greatest benefits in marginalized populations at greatest risk for these exposures, promoting health equity through biologically informed treatments as strategies to ameliorate the structural contributors to SDOH continue to evolve with time.