Approved Research

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

Lay summary

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.

Scope extension:

Research Question (R.Q.)1. Are there and which pathways explain racial/ethnic disparities in Alzheimer's Disease(AD)/all-cause dementia (DEMENTIA)?

1.1. Test racial/ethnic disparities in incident AD/DEMENTIA, and related pathways.

1.2. Test role played by infectious burden.

R.Q.2. Is Helicobacter pylori sero-positivity associated with AD/DEMENTIA and sMRI/dMRI outcomes?

2.1. Determine whether Helicobacter pylori, with/without other infections, is associated with AD/DEMENTIA.

2.2. Determine the metabolome's mediating effects and association with sMRI/dMRI outcomes. 

2.4 Determine Helicobacter pylori's association with sMRI/dMRI outcomes.

R.Q.3. Are genetically determined metabolites and infections associated with AD/DEMENTIA differentially by race?

3.1 Generalized serum uric acid (SUA)/polygenic risk score (PRS); Replication attempt for SUA/PRS in African Americans (HANDLS study).

3.2 Mendelian Randomization (MR) study for SUA and AD/DEMENTIA across race groups, using generalized SUA/PRS.

3.3 Association of Apolipoprotein E (APOE) with lipid metabolites across race.

3.4. MR study by race for APOE, selected serum lipid metabolites and AD/DEMENTIA.

4.5. GWAS and PRS for Helicobacter pylori sero-positivity; Predict metabolites with Helicobacter pylori PRS.

4.6. Conduct a MR of Helicobacter pylori PRS--> related metabolites-->AD/DEMENTIA.

R.Q.4. Is H. pylori associated with AD/DEMENTIA (or neuroimaging markers), conditional on  APOE/SUA PRS?

4.1. Test whether H. pylori sero-positivity/PRS interacts with APOE/SUA PRS affecting AD/DEMENTIA.

4.2. 4.1. for sMRI/dMRI outcomes.

R.Q.5. Is Life's essential 8 a moderator in the associations of infection burden (based on hospitalization data), or persistent infection burden (based on serology data) and dementia traits?

5.1. Test whether infection burden or persistent infection burden are associated with AD/DEMENTIA differentially across Life's essential 8 measure of cardiovascular health.

5.2. Conduct mendelian randomization study for LE8 and sMRI/dMRI outcome. Test interaction by infection burden. 

5.3. Conduct mendelian randomization study for periodontal disease and dementia incidence. Test interaction by Life's essential 8.

5.4. 5.2. for sMRI/dMRI outcomes.

R.Q.6 Are race/ethnicity and AD PRS independently associated with dementia traits?

6.1. Test whether race/ethnicity an AD PRS  are independently associated with AD/DEMENTIA, differentially across sex.

6.2. Does AD PRS moderate the association between infection and AD/DEMENTIA.

6.3. 6.1. and 6.2. for sMRI/dMRI outcomes.

R.Q.7.  R.Q.1 for sMRI/dMRI outcomes.

R.Q.8. Are genetically determined nutritional biomarkers previously linked to H. pylori infection, related to dementia traits?

8.1. Vitamin D receptor and megalin gene SNPs vs. AD/DEMENTIA incidence; sMRI/dMRI outcomes.

8.2. MTHFR and other One-carbon metabolism SNPs vs. AD/DEMENTIA incidence; sMRI/dMRI outcomes.

8.3. Red cell distribution width and other anemia-related and blood traits resulting from H. pylori infection, mendelian randomization vs. AD/DEMENTIA; sMRI/dMRI outcomes.