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

TAS2R38 is a taste receptor implicated in innate immunity. Identifying its genetic connection with Alzheimer's disease (AD) could aid in developing new drugs or repurposing existing ones for treatment.

We examined the relationship between TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 2,342). We investigated molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues from the Religious Orders Study/Memory and Aging Project (ROSMAP) (n = 947). We evaluated whether FDA-approved drugs targeting the identified gene could reduce dementia risk using 1:1 propensity score-matched groups in the National Alzheimer's Coordinating Center (NACC) study, comparing cognitive performance between drug-taking and non-taking patients with linear mixed-effects models (n = 76).

TAS2R38 supertasters were linked to reduced AD risk with advancing age in various AD biomarkers (P < 0.001). eQTL analysis connected the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (P < 0.001). Elevated MGAM expression was also associated with more severe Tau burdens (P < 0.05). A significant group difference was observed in clinical dementia rating (CDR) progression (P < 0.001) in various domains for individuals taking MGAM-inhibiting diabetes drugs (Acarbose and Miglitol) compared to the non-taking group.

The genetic association between TAS2R38 and AD biomarkers implicates MGAM as a novel drug target with existing FDA-approved inhibitors. This supports the potential of TAS2R38 haplotypes in guiding precision drug repurposing strategies for AD, warranting clinical trials.