This study, conducted by Michael E. Belloy, PhD, and colleagues, is the first large-scale X chromosome-wide association study (XWAS) of Alzheimer's disease (AD). The researchers aimed to investigate the role of the X chromosome in AD genetics, as the X chromosome makes up 5% of the human genome and carries a significant number of genes expressed in the brain. This study used data from multiple large genetic consortia and biobanks, including the Alzheimer's Disease Genetics Consortium, the Alzheimer's Disease Sequencing Project, the UK Biobank, the Finnish Health Registry, and the US Million Veterans Program. In total, the study included over 1.1 million participants, with approximately 138,000 Alzheimer's cases. The analysis identified six genetic loci on the X chromosome that were associated with AD risk, with the SLC9A7 locus emerging as a novel risk gene. 

The findings suggest that SLC9A7 plays a role in regulating pH in Golgi secretory compartments, which may affect amyloid β accumulation-a key feature of Alzheimer's disease pathology. The study also revealed that four of the identified loci showed evidence of escaping X chromosome inactivation (XCI), a process that typically silences one of the X chromosomes in women to balance gene expression with men, who only have one X chromosome. These findings are important for understanding the potential sex-based differences in AD, as women tend to have a higher prevalence of AD and potentially different genetic susceptibilities to the disease. The researchers emphasize that the escape from XCI could be an important mechanism underlying these sex differences.

Overall, the study sheds light on the previously underexplored role of the X chromosome in Alzheimer's disease. The discovery of the SLC9A7 locus as a novel AD risk gene provides a potential target for future therapeutic interventions. Additionally, the findings underscore the need for further research into the genetic mechanisms that contribute to sex differences in AD, as well as the broader role of X chromosome genetics in neurodegenerative diseases.