RPTOR is an Alzheimer’s Disease susceptibility gene associated with Alzheimer’s Disease risk factors BMI and infectious encephalitis

Abstract

Background: In comparison to persons who did not have viral encephalitis, people with viral encephalitis had a later-life risk of Alzheimer's disease (AD) that was 31 times higher. In a previous study, we were able to confirm the association of viral encephalitis with AD and suggest that West Nile Virus infection is a significant AD risk factor. A genome wide association study (GWAS) with UK Biobank data revealed that the gene RAR Related Orphan Receptor B (RORB), previously linked to AD, is significantly associated with viral encephalitis. Methods: In the current study we used data from PheWeb to identify genes other than RORB that might be involved in both infectious encephalitis and AD. We used UK Biobank data to examine gene expression and phenotypic expression. Results: PheWeb identified additional genes associated with both infectious encephalitis and AD. RPTOR, a gene associated with the mTOR pathway, emerges as significant. Analyses of UK Biobank data reveal the impact of RPTOR on AD risk, with carriers of the minor allele A exhibiting decreased prevalence in subjects under age 55. Further analysis demonstrates that RPTOR genotypes influence Body Mass Index (BMI) in subjects of all ages, with carriers of the minor allele A having lower BMI. Logistic regression analyses confirm the association between reduced BMI and increased AD risk, along with the established factor of age. Conclusion: RPTOR may represent an early onset AD gene, though mTOR's role in AD and BMI is complex. Nevertheless, RPTOR and mTOR could represent potential therapeutic targets for AD.