The role of APOE ε4 in modulating the relationship between non-genetic risk factors and dementia: a system review and meta-analysis.

BACKGROUND

The ε4 allele of the apolipoprotein E gene (APOE ε4) is the strongest genetic risk factor for dementia. However, it remains unclear whether APOE ε4 status modulates the associations of non-genetic risk factors and dementia risk. This study aims to comprehensively evaluate this potential modulating role.

METHODS

A systematic search of electronic databases was conducted up to June 2023. Population-based longitudinal studies were included if they reported associations of risk factors with all-cause dementia (ACD) or Alzheimer's disease (AD) stratified by APOE ε4 status. Subgroup and meta-regression analyses were performed to test stratification effects by APOE ε4.

RESULT: A total of 170 studies (173 factors) were included, with 48 factors for meta-analyses. Meta-regression confirmed significant modification effect by APOE ε4 status for nine risk factors. Stronger associations in APOE ε4 carriers were found for nonsteroidal anti-inflammatory drugs, statins, frequent drinking, and high systolic blood pressure; in noncarriers, stronger associations were observed for light-to-moderate alcohol consumption, female sex, physical activity, diabetes, and loneliness. Diabetes specifically increased AD risk only in APOE ε4 noncarriers. Additionally, the subgroup analyses stratified by APOE ε4 status indicated that nine other factors may influence risk differentially between carriers and noncarriers, though the associations were not significant in meta-regression (vitamin E intake, heart failure, serum neurofilament light chain, serum testosterone, agitation, air NO2 concentration, ever smoker, current smoker, and head injury).

CONCLUSION

Evidence from the current investigation suggests that APOE ε4 defines distinct etiological pathways for dementia, underscoring the promise of genotype-tailored prevention strategies.