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Basic Science and Pathogenesis
Alex G Contreras1,2, Skylar Walters3, Jaclyn M Eissman4
1Vanderbilt Memory & Alzheimer's Center, Nashville, TN, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
This study investigated how genetic variants (SNPs), sex, and APOE-ε4 status interact to affect memory in Alzheimer's disease (AD). Preliminary findings suggest a potential link between the HGSNAT gene and APOE-ε4 in cognitive decline, particularly in males.
Area of Science:
- Genetics
- Neuroscience
- Alzheimer's Disease Research
Background:
- Alzheimer's disease (AD) disproportionately affects women, with known sex-specific APOE effects on cognition.
- The interaction between APOE genotype, sex, and single nucleotide polymorphisms (SNPs) on cognitive domains is not well understood.
Purpose of the Study:
- To investigate the three-way interaction of SNP×APOE-ε4×sex on memory using a genome-wide association study (GWAS) meta-analysis.
- To identify novel genetic variants and biological pathways influencing cognitive performance modulated by sex and APOE status.
Main Methods:
- Conducted a GWAS meta-analysis using harmonized memory data from six cohorts, including 33,440 European-ancestry individuals.
- Focused on the SNP×APOE-ε4×sex interaction for memory and performed stratified main-effects GWAS by sex and APOE-ε4 status.
Main Results:
- Identified 112 suggestive SNPs for the three-way interaction, with one locus intronic to HGSNAT, a gene linked to lysosomal function.
- Discovered four genome-wide significant main-effect signals for memory in male APOE-ε4 carriers, with rs76307224 showing the strongest association (P=2.18×10⁻¹⁰).
- Observed no significant associations in females, irrespective of APOE genotype.
Conclusions:
- Preliminary findings suggest a potential novel connection between HGSNAT, APOE-ε4, and cognitive decline, possibly involving lysosomal dysfunction.
- The study highlights the importance of considering sex and APOE status when analyzing genetic associations with cognitive performance.
- Future analyses with larger, diverse datasets and other cognitive domains will enhance understanding of AD risk and generalizability.
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