SLC9A7 has been identified as a novel genetic risk locus on the X chromosome linked to Alzheimer’s disease risk, according to a recent study.

The large-scale X chromosome-wide association study—published in JAMA Neurology—analyzed genetic data from 1,152,284 participants of non-Hispanic White European ancestry, including 138,558 participants with Alzheimer's disease (AD). The study included 664,403 female participants (57.7%) and 487,881 male participants (42.3%).

Researchers identified six independent genetic loci linked to AD which met the threshold for X chromosome–wide significance (P < 1 × 10⁻⁵), with four demonstrating associations between genetic variants and gene expression in brain and nonbrain tissues. The strongest association identified was within the intron of the SLC9A7 gene, which reached genome-wide significance with an odds ratio of 1.03 (95% confidence interval = 1.02-1.04; P < 5 × 10⁻⁸). The locus implicated in pH homeostasis may influence amyloid β accumulation—a hallmark of AD pathology.

The study also explored sex-specific genetic associations. Four of the identified loci displayed evidence of escaping X chromosome inactivation (XCI), contributing to the understanding of sex-based differences in AD prevalence and progression. The role of XCI escape in females may help explain the higher incidence and severity of AD in women.

While these findings provide an important contribution to understanding AD genetics, the effect sizes of the identified loci were modest. The study authors concluded, "Altogether, these results suggest that X chromosome genetics likely play a role in AD sex differences and warrant further investigation, opening the door to sex-specific pathogenic pathways and associated drug targets."

Full disclosures can be found in the published study.