TAS2R38-Linked MGAM Expression in Alzheimer's Disease: A Novel Target for Precision Drug Repurposing

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• The TAS2R38 gene encodes a taste receptor involved in innate immunity.
• Alzheimer's disease (AD) pathogenesis is complex, with genetic factors playing a significant role.
• Identifying novel genetic associations could lead to new therapeutic strategies for AD.

Purpose of the Study:

• To investigate the genetic relationship between TAS2R38 variants and Alzheimer's disease risk.
• To explore the molecular mechanisms underlying this association.
• To evaluate the potential of existing drugs targeting identified pathways for AD treatment.

Main Methods:

• Utilized linear mixed-effects models with data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to assess AD risk and TAS2R38 variants.
• Employed RNA-sequencing data from the ROSMAP study to identify expression quantitative trait loci (eQTLs) for molecular mechanism investigation.
• Applied propensity score matching in the National Alzheimer's Coordinating Center (NACC) study to compare cognitive outcomes in patients taking MGAM-inhibiting drugs versus controls.

Main Results:

• TAS2R38 supertaster variants were associated with reduced AD risk and improved AD biomarkers with age.
• eQTL analysis revealed a link between the TAS2R38 nontaster allele and increased MGAM gene expression in AD-affected brain regions.
• Individuals taking MGAM-inhibiting diabetes drugs (Acarbose, Miglitol) showed significantly different clinical dementia rating progression compared to non-takers.

Conclusions:

• The genetic link between TAS2R38 and AD biomarkers highlights MGAM as a potential therapeutic target.
• Existing FDA-approved MGAM inhibitors show promise for repurposing in AD treatment strategies.
• TAS2R38 haplotypes may guide precision medicine approaches for Alzheimer's disease.