A Favorable Modifiable Risk Factor Profile Mitigates Polygenic Risk for Alzheimer’s Disease and Related Dementia

Background A recent Lancet Commission estimated that up to 45% of Alzheimer’s Disease and Related Dementias (ADRD) cases could be prevented by addressing modifiable lifestyle risk factors. Meanwhile, genome-wide association studies (GWAS) have shown that common genetic variants also account for substantial ADRD risk. Whether a favorable lifestyle can offset risk in genetically predisposed individuals remains unclear. Methods We conducted a retrospective cohort study of 105,886 participants from the All of Us Research Program enrolled between 2018–2023. Participants were over age 49, assigned male or female at birth, of European ancestry, and without ADRD at baseline. ADRD diagnoses were identified via electronic health records (EHR). Fourteen potentially modifiable risk factors for ADRD were assessed using surveys, EHR records, and wearable data. Genetic risk was quantified as a polygenic risk score (PRS) based on 81 independent GWAS loci and APOE ε4 genotype. Results Overall, 967 incident ADRD events occurred over a median follow-up of 3.7 years. Ten out of 13 modifiable risk factors were significantly associated with ADRD. When grouped into risk factor profiles, intermediate and unfavorable modifiable risk factor scores were associated with substantially higher ADRD risk (HR 3.07, 95% CI 2.47–3.83; HR 8.01, 95% CI 6.39– 10.05, respectively) compared to a favorable lifestyle; APOE ε4 dosage and polygenic risk score were also independently associated with ADRD risk. Among individuals in the highest polygenic risk group, a favorable lifestyle reduced ADRD risk from HR 18.63 (95% CI 10.25–33.86) to 1.90 (95% CI 0.94–3.81), whereas APOE ε4 homozygotes remained at elevated risk even with a favorable lifestyle (HR 6.52, 95% CI 2.97–14.33). Conclusions Our data suggest ADRD risk is driven more by modifiable risk factors and APOE genotype than polygenic risk score. Future genomic-informed risk assessments for ADRD should calibrate their findings to accurately identify high-risk individuals.