Background <p>The ε4 allele of&#xa0;the apolipoprotein E gene&#xa0;(<i>APOE</i> ε4) is the strongest genetic risk factor for dementia. However, it remains unclear whether <i>APOE</i> ε4 status modulates the associations of non-genetic risk factors and dementia risk. This study aims to comprehensively evaluate this potential modulating role.</p> Methods <p>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 <i>APOE</i> ε4 status. Subgroup and meta-regression analyses were performed to test stratification effects by <i>APOE</i> ε4.</p> Result <p>A total of 170 studies (173 factors) were included, with 48 factors for meta-analyses. Meta-regression confirmed significant modification effect by <i>APOE</i> ε4 status for nine risk factors. Stronger associations in <i>APOE</i> 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 <i>APOE</i> ε4 noncarriers. Additionally, the subgroup analyses stratified by <i>APOE</i> 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).</p> Conclusion <p>Evidence from the current investigation suggests that <i>APOE</i> ε4 defines distinct etiological pathways for dementia, underscoring the promise of genotype-tailored prevention strategies.</p>