APOE and Alzheimer's disease and related dementias risk among 12,221 Hispanics/Latinos

BACKGROUND: Effect of apolipoprotein E (APOE) on Alzheimer's disease and related dementias (ADRD) risk is heterogeneous across populations, with scarce data on Hispanics/Latinos. METHODS: APOE genotype was studied in 12,221 Hispanics/Latinos (per cohort and via metanalysis): Caribbean-Hispanics, Mexicans, Mexican-Americans, and Peruvians/Bolivians. A subsample had longitudinal assessment and plasma p-tau. We tested the modifying effects of global and local ancestries. Results were replicated in an independent Peruvian cohort and brain samples. RESULTS: APOE ε4 effect was strongest in Peruvians/Bolivians (odds ratio [OR] = 6.13, 95% confidence interval [CI] = 2.71–13.83), followed by Mexicans (OR = 4.31, 95% CI = 1.58–11.74), Mexican-Americans (OR = 3.06, 95% CI = 2.04–4.59), and Caribbean-Hispanics (OR = 2.22, 95% CI = 1.99–2.48). Meta-analyses showed OR = 2.32 (95% CI = 2.09–2.57) and OR = 0.81 (95% CI = 0.68–0.97) for the ε4 and ε2 allele, respectively. The APOE ε4 effect was replicated independently in Peruvians (OR = 5.06, 95% CI = 2.48–10.70). ε4 carriers displayed higher ADRD conversions and p-tau levels. Global and local ancestries did not modify ADRD risk, and they were associated with Braak stage. DISCUSSION: APOE shows a heterogeneous effect on ADRD risk in our Hispanics/Latinos sample, the largest to date. Highlights: The apolipoprotein E (APOE) ε4 effect is stronger in Peruvians/Bolivians than in other Hispanic/Latino groups. The strong APOE effect size in Peruvians and Bolivians was replicated in a second independent Peruvian cohort. Meta-analysis for ε4 and ε2 confirmed a significant association with Alzheimer's disease and related dementias (ADRD). Global and local ancestry do not modify the association between APOE genotype and ADRD.