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

Abstract

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.

Keywords: ADRD; APOE; Hispanic/Latino population; admixture; health disparities.

FIGURE 1

Principal component analyses for the four Hispanic/Latino cohorts, along with three reference populations from the Human Genome Diversity Project (European [HGDP‐EUR], African [HGDP‐AFR], Native American [HGDP‐NAA]). The three‐dimensional axes represent the three principal components (PCs) used to plot genetic ancestry proportions. The colors of each point (each point represents an individual) correspond to the different cohorts, including the reference population panels (light blue = Africans from the Human Genome Diversity Project; green = Europeans from the Human Genome Diversity Project; red = Native Americans from the Human Genome Diversity Project; dark blue = Caribbean Hispanics; fuchsia = Mexican Americans; yellow = Mexicans; black = Peruvians).

FIGURE 2

Mixed‐effects Cox model in WHICAP+EFIGA. APOE ε4 carriers versus non‐carriers are plotted over the follow‐up time.

FIGURE 3

Meta‐analysis and forest plot for ε4 (upper panel) and ε2 (lower panel) alleles. The plot details the beta coefficients (BETAs), standard errors (SEs), odd ratios (ORs), 95% confidence intervals (CIs), and the individual study weights according to their contributions to the pooled estimates. The horizontal lines represent the study's 95% CIs, with each end of the line representing the boundaries of the CI. A black dot represents the point estimate of the study, and it also provides a visual representation of the size of the study (the largest dot corresponds to a larger sample size). The dotted vertical lines are drawn at the value of the overall common effect. The diamond below the studies represents the overall pooled effect.