ABSTRACT With an increasing proportion of the population at older ages (i.e., the ‘graying of America’), there is a growing prevalence of Alzheimer’s Disease and Related Dementias (ADRDs). By the year 2030, the number of “oldest” Americans is expected to grow by 81% among non-Hispanic Whites (NHWs), 131% among African Americans, 328% among Hispanics and 285% among Asians/Pacific Islanders. Similarly, the direct and indirect cost of AD/ADRD is estimated to be over $450 billion by the year 2030. The mortality related to dementias have also increased by 71% from the year 2000 to 2013. Although the incidence and prevalence of dementia is expected to increase significantly across all racial and ethnic groups. There is existing racial/ethnic disparity in the incidence and prevalence of ADRDs. In general, the prevalence of all dementias is 2.5-fold higher among African Americans compared to (NHWs), with recent prospective studies, showing that African Americans have a significantly higher incidence of dementia and cognitive impairment even after adjusting for all relevant risk factors. While the exact reasons for the existing racial disparity in AD/ADRD is not clearly known, one potential reason, which is the focus of this proposal, is the sickle cell mutation (HbS), which is prevalent in individuals of African ancestry but almost entirely absent among (NHWs). Our reasoning is based on two points (1) adjustment for traditional dementia risk factors did not attenuate the observed disparity, and (2) despite the higher increase in the proportion of “oldest” Americans among Asians/Pacific Islanders compared to NHWs (265% vs. 81%), the incidence of dementia in both racial/ethnic groups is on par with each other, thus a higher proportion of oldest individual is not likely the reason for the disparity. Given the high prevalence of the APOE ε4 risk allele (~37%) among individuals of AAs and the fact that co-inheritance of any combination of the APOE ε4 risk allele (i.e. 2/4, 3/4 or 4/4) along with SCT is a common occurrence, as shown by our preliminary data, we hypothesize that the combined presence of SCT and APOE ε4 ADRD risk allele, will lead to earlier onset and/or more severe cognitive deficit, with accompanying increase in neuroinflammation and abnormal brain lipidomics profile compared to controls. The findings from this proposal will provide insight into the mechanisms by which SCT modifies the impact of APOE ε4 on ADRD risk, and thus contributes to differences in cognitive deficit and dementia observed in our prior study among African Americans. This could allow us to address racial disparity in cognitive deficit. Further, results from this study could provide a model system for the testing of therapies aimed specifically at reducing racial/ethnic disparity in dementia therapy in people of African descent.