Dissecting racial/ethnic disparities in dementia traits through socio-economic, lifestyle, cardio-metabolic risk and infectious agents, with focus on Helicobacter pylori sero-positivity

The global all-cause dementia (DEMENTIA) prevalence (>60y) is estimated at ~4.7%, with 60-80% caused by Alzheimer’s Disease (AD), a multi-factorial neurodegenerative disorder manifesting as progressive episodic memory and other cognitive domain decline. Racial/ethnic, gender and socio-economic disparities in dementia risk have been reported. In the absence of a cure, modifiable and non-modifiable risk and protective factors have been identified with wide racial/ethnic disparities. We recently examined pathways among US older adults explaining racial/ethnic disparities in AD/DEMENTIA overall and among men and women separately. We attempt at replicating US findings, using a similar structural equation modeling framework, including socio-economic, lifestyle and health-related mediators, thus ascertaining biological plausibility across cultural settings. Racial and socio-economic disparities in the infectious burden was reported. Among those, H. pylori was recently shown to trigger cognitive impairment and early markers of neurodegeneration, particularly in men. The mediating effect of the infectious burden will be tested separately, to explain both racial/ethnic and socio-economic disparities in AD/DEMENTIA incidence. We will attempt to replicate our US findings, by examining the independent association of H. pylori with those outcomes brain MRI early markers of neurodegeneration and their interaction with other infections in those associations. We also previous examined the interaction between H. pylori and periodontitis in relation to AD/DEMENTIA. In this project, in addition to attempting replication, we further examine those interaction in relation to brain MRI markers of neurodegeneration, while assessing mediation through the metabolome. Given APOE genotype’s strong predictive value for AD/DEMENTIA, several mendelian randomization (MR) studies will test whether genetically determined lipid metabolites are related to these outcomes. APOE genotype’s differential association with lipids across race will also be tested, while assessing Apolipoprotein E (APOE) genotype’s interaction with H. pylori sero-positivity in relation to AD/dementia and brain MRI outcomes. The association between SUA with age-related cognitive decline has been examined, reporting both adverse and protective effects. Whether genetically determined SUA is linked to AD/DEMENTIA risk remains uncertain. SUA’s interaction with H. pylori sero-positivity vs. AD/DEMENTIA and early brain MRI markers of neurodegeneration merits investigation. Following a similar methodology as for lipids/APOE, we will test whether genetically determined SUA interacts with H. pylori to determine AD/DEMENTIA risk. Finally, we will generate a polygenic risk score (PRS) for H. pylori, testing it against the metabolome, and then will conduct MR studies of H. pylori PRS, related metabolites and AD/DEMENTIA and brain MRI outcomes.