RPTOR Is an Alzheimer’s Disease Susceptibility Gene Associated with the Risk Factors Body Mass Index 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) is significantly associated with viral encephalitis. Objective: To use data from the 8 PheWeb datasets to try to identify genes other than RORB that might be involved in both infectious encephalitis and AD. Methods: PheWeb includes data from UKBB and 5 other databanks. 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. Conclusions: RPTOR may represent an AD gene, though mTOR’s role in AD and BMI is complex. Nevertheless, RPTOR and mTOR could represent potential therapeutic targets for AD.