Introduction: Growing evidence highlights a potential genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD); however, the role of the PD risk variant rs6430538 in AD remains unclear.

Methods: In Stage 1, we investigated the risk associated with the rs6430538C allele in seven large-scale AD genome-wide association study (GWAS) cohorts. In Stage 2, we performed expression quantitative trait loci (eQTL) analysis to calculate the cis-regulated effect of rs6430538 on TMEM163 in both AD and neuropathologically normal samples. Stage 3 involved evaluating the differential expression of TMEM163 in 4 brain tissues from AD cases and controls. Finally, in Stage 4, we conducted a transcriptome-wide association study (TWAS) to identify any association between TMEM163 expression and AD.

Results: The results showed that genetic variant rs6430538C allele might increase the risk of AD. eQTL analysis revealed that rs6430538 up-regulated TMEM163 expression in AD brain tissue, but down-regulated its expression in normal samples. Interestingly, TMEM163 showed differential expression in entorhinal cortex (EC) and temporal cortex (TCX). Furthermore, the TWAS analysis indicated strong associations between TMEM163 and AD in various tissues.

Discussion: In summary, our findings suggest that rs6430538 may influence AD by regulating TMEM163 expression. These discoveries may open up new opportunities for therapeutic strategies targeting AD.