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. 2025 Jun 19;11(2):e70124.
doi: 10.1002/trc2.70124. eCollection 2025 Apr-Jun.

Alzheimer's disease genetic risk: Top African American risk allele frequencies and genetic architecture among Mexican-, African-, and non-Hispanic White Americans

Mohammad Housini  1   2   3 , Zhengyang Zhou  3   4 , Lubnaa Abdullah  3 , Gita Pathak  5 , Reem Ayoub  2 , John Gutierrez  6 , Shea Andrews  7 , Nicole Phillips  3   8 , Sid O'Bryant  2   3 , Robert Barber  2   3 ; HABS‐HD Study Team
Affiliations

Alzheimer's disease genetic risk: Top African American risk allele frequencies and genetic architecture among Mexican-, African-, and non-Hispanic White Americans

Mohammad Housini et al. Alzheimers Dement (N Y). .

Abstract

Introduction: Alzheimer's disease (AD) continues to be the sixth leading cause of death in the United States. Significant efforts are spent researching etiology and potential management strategies. Although minorities face a higher disease burden and are anticipated to make up 43% of the US population by 2060, most literature on inherited AD risk has been derived from studying European ancestry. Here we evaluate frequencies of top AD risk alleles for late-onset AD (LOAD) in African- (AA), Mexican- (MA) and non-Hispanic White (NHW)-American participants enrolled in the Health & Aging Brain Study-Health Disparities (HABS-HD) cohort to determine ethnicity-specific differential genetic architecture.

Methods: Using DNA extracted from this community-based diverse cohort (N = 3207), we calculated the genotype frequencies in each population to determine whether a significant difference is detected among the three populations. DNA genotyping was performed per manufacturer's protocols. Imputation was used for single nucleotide polymorphisms (SNPs) that were not directly genotyped. Statistical analysis was performed using R Studio.

Results: Genotype frequencies for 12 out of 15 SNPs (2 apolipoprotein E [APOE] variants, SIPA1L2, PIK3C2G, GPC6, RBFOX1, ABCA7, VRK3, ALCAM, EDEM1, NSG/MSX2, and WDR70) differed significantly between groups.

Discussion: This analysis expands on our previous study supporting the notion that genetic risk for AD is heterogeneous across racial and ethnic populations. Our results continue to demonstrate the valuable nature of diversity in genetic risk investigations and suggest the importance of including diverse and underrepresented racial and ethnic populations in medical research. Perhaps the most interesting finding is observed in the SNPs not found to be significantly different between groups, indicating there may be shared pleiotropic gene architecture across ethnicities.

Highlights: Alzheimer's disease (AD) burden is rapidly increasing in the United States; minorities are disproportionally affected.We investigate genetic health disparities in our community-based diverse cohort.Twelve of 15 evaluated single nucleotide polymorphisms significantly differ among ethnicities in the Health & Aging Brain Study-Health Disparities.

Keywords: African American; Alzheimer's disease; Hispanic; Mexican American; dementia; diversity; genetics; health disparities; mild cognitive impairment.

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Conflict of interest statement

Authors do not report any conflicts of interest relating to the work in this manuscript. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
A, APOE ε4 positivity distribution and carrier status count in HABS‐HD. B, APOE genotype frequency. C, APOE linkage disequilibrium heatmap. AA, African American; APOE, apolipoprotein E; HABS‐HD, Health & Aging Brain Study–Health Disparities; MA, Mexican American; NHW, non‐Hispanic White.
FIGURE 2
FIGURE 2
A, SNPs with significantly different genotype frequencies and (B) SNPS without any significant genotype frequency differences. AA, African American; MA, Mexican American; NHW, non‐Hispanic White; SNP, single nucleotide polymorphism.
FIGURE 3
FIGURE 3
Representative linkage disequilibrium heatmaps, continued in Figures S1 and S2 in supporting information.
See this image and copyright information in PMC

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