APOE alleles’ association with cognitive function differs across Hispanic/Latino groups and genetic ancestry in the study of Latinos‐investigation of neurocognitive aging (HCHS/SOL)

Abstract

Introduction Apolipoprotein E (APOE) alleles are associated with cognitive decline, mild cognitive impairment (MCI), and Alzheimer's disease in Whites, but have weaker and inconsistent effects reported in Latinos. We hypothesized that this heterogeneity is due to ancestry‐specific genetic effects. Methods We investigated the associations of the APOE alleles with significant cognitive decline and MCI in 4183 Latinos, stratified by six Latino backgrounds, and explored whether the proportion of continental genetic ancestry (European, African, and Amerindian) modifies these associations. Results APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P‐value = 0.03), with the strongest association in Cubans (OR = 1.46, P‐value = 0.007). APOE‐ε2 was associated with decreased risk of MCI (OR = 0.37, P‐value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline. Discussion Results suggest that APOE alleles' effects on cognitive outcomes differ across six Latino backgrounds and are modified by continental genetic ancestry.

Polygenic Risk Scores for Alzheimer’s Disease and Mild Cognitive Impairment in Hispanics/Latinos in the U.S: The Study of Latinos – Investigation of Neurocognitive Aging

“…Table 4 reports the association of the AD PRS and of APOE - ϵ 4 and APOE - ϵ 2 allele counts, in a model that accounted for all these genetic components together, with MCI. APOE - ϵ 4 and APOE - ϵ 2 alleles were generally unassociated with MCI, as we previously shown in this population (Granot-Hershkovitz et al 2020). However, in the model with FINNGEN PRS, both APOE alleles were protective against MCI.…”

“…At the same time, the APOE - ϵ 4 allele count was not associated with MCI while the FINNGEN PRS was. This adds to a cumulative evidence about differences in the APOE gene region architecture and association with cognitive aging phenotypes by genetic ancestry (Blue et al 2019, Cornejo, Granot-Hershkovitz et al 2020, Teruel et al 2011). Other investigations focused on the APOE alleles themselves, this is the first time where we see evidence of heterogeneity in a combination of APOE -related SNPs, rather than APOE - ϵ 4 and ϵ 2 alleles.…”

“…Rates of Alzheimer’s disease and related dementia (ADRD) and mild cognitive impairment (MCI), which often precedes ADRD, are higher in Hispanics/Latinos compared to European Americans (Choi et al 2018a, Mayeda et al 2016, Weden et al 2017). However, the strongest known genetic risk factors for ADRD, the APOE - ϵ 4 allele (Genin et al 2011), has weaker association in Hispanics/Latinos compared to individuals of European ancestry (Farrer 1997), and was not associated with MCI in recent studies from the Study of Latinos – Investigation of Cognitive Aging (SOL-INCA) (González et al 2019b, Granot-Hershkovitz et al 2020). Polygenic Risk Score (PRS) are aggregated summaries of genetic data, generally defined as weighted sums of counts of risk alleles for a particular health outcome across the genome.…”

Apolipoprotein E ε4 Allele-Based Differences in Brain Volumes Are Largely Uniform Across Late Middle Aged and Older Hispanic/Latino- and Non-Hispanic/Latino Whites Without Dementia

“…As noted earlier, this may reflect a survivor effect, which outweighs the negative impacts of APOE ε4, or may reflect a change from a harmful to a beneficial role of the APOE ε4 status among the oldest. Alternatively, genetic ancestry may influence the impact of the APOE ε4 status on Hispanic/Latino cognitive aging (Blue et al, 2019;Granot-Hershkovitz et al, 2020). Recent data suggest that, first, greater Amerindian genetic ancestry is associated with protection against APOE ε4-related cognitive declines (Granot-Hershkovitz et al, 2020).…”

“…Alternatively, genetic ancestry may influence the impact of the APOE ε4 status on Hispanic/Latino cognitive aging (Blue et al, 2019;Granot-Hershkovitz et al, 2020). Recent data suggest that, first, greater Amerindian genetic ancestry is associated with protection against APOE ε4-related cognitive declines (Granot-Hershkovitz et al, 2020). Second, education may be interacting with APOE ε4 to impact episodic memory (Christensen et al, 2008) as well as to diminish the association of APOE ε4 and global cognition when it is taken into account (Winnock et al, 2002).…”