Genome-wide association studies of Alzheimer’s disease and related disorders stratified by sex, onset age, and Apolipoprotein E genotype reveal novel risk loci in African Americans

TL;DR

This study identifies new genetic risk factors for Alzheimer's disease in African Americans by analyzing data stratified by age, sex, and APOE genotype.

Contribution

The study reveals novel risk loci in African Americans through stratified genome-wide analyses that were previously underpowered.

Findings

A novel risk locus near EPHA5 was found in individuals with early-onset Alzheimer's disease.

GRIN3B showed significant association in females and TSPEAR in APOE-ε4 non-carriers.

Stratified analyses highlight genetic heterogeneity in dementia risk among African Americans.

Abstract

Alzheimer’s disease (AD) risk variants have been identified in European ancestry cohorts that have stronger effects at certain ages, in individuals with a specific sex, or in those with specific isoforms of APOE, the strongest AD risk locus. However, sample sizes in African ancestry (AA) cohorts have been underpowered to perform stratified analyses.

We generated genome-wide association study datasets stratified by sex, age at onset (< 75 vs ≥ 75), and APOE-ε4 carrier status in AA cohorts from MVP and the Alzheimer’s Disease Genetics Consortium (ADGC). Outcomes in MVP were AD and related dementias (ADRD; n = 4073 cases and 19,648 controls) and proxy dementia (i.e., reported dementia in a parent, n = 6216 cases and 21,566 controls) while ADGC analyses examined AD (n = 2425 cases and 5069 controls). The proxy dementia GWASs were included in the sex-stratified meta-analysis corresponding to the sex of the affected parent. The top genes were tested for differential expression in AA brain tissue.

In addition to the APOE region, genome-wide significant associations were observed in an intergenic region near the EPHA5 gene (rs141838133, p = 2.19 × 10–8) in individuals with onset < 75 years, in GRIN3B near the known AD risk gene ABCA7 (rs115882880, p = 3.83 × 10–8) in females, and near TSPEAR (rs139130053, p = 4.27 × 10–8) in APOE-ε4 non-carriers. EPHA5 regulates glucose homeostasis, and ephrin receptors modify the strength of existing synapses in the brain and in pancreatic islets. It is unclear whether GRIN3B represents a locus distinct from ABCA7. Rs115882880 was a significant eQTL for GRIN3B but not ABCA7 in AA brain samples. TSPEAR regulates Notch signaling but has not been linked to neuronal function.

Age, sex, and APOE-stratified analyses of dementia in AA participants from two cohorts revealed potential new associations. Stratified analyses may yield critical information about the genetic heterogeneity underlying dementia risk and lead to advances in precision medicine.

The online version contains supplementary material available at 10.1186/s13195-025-01782-y.

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