The effects of MGAM inhibitors on cognitive decline in Alzheimer's Disease cohorts

The National Alzheimer's Coordinating Center (NACC) has coordinated all the Alzheimer's Disease Research Centers (ADRCs) across the US to build one of the world’s largest and most comprehensive datasets on Alzheimer’s disease and related dementias (AD/ADRD). To utilize these datasets for precision drug repurposing, we are requesting the genetic data profiled by the 15 rounds of genomic array of ADC since it covers large proportions of the NACC subjects whose genetic data like APOE are not available otherwise. We are proposing the following study:

1. Harmonize the genetic data across the 15 rounds of microarrays. Since these arrays were from different platforms profiled for different subjects, we plan to harmonize the genomic data to the reference genome GPCh38 for all the available subjects. Together with other subjects whose genetic data were available from ADSP WGS, we are aiming to impute the missing APOE genotypes in these subjects in any datasets which makes the APOE4 status available to all the subsequent studies.

2. Focus on the study of the TAS2R38 variants and their relationships with AD risks. Using the harmonized genetic data, we are investigating the relationship of TAS2R38 supertaster variants with the cognitive functions of the subjects within the ADC cohorts. Our preliminary data shows TAS2R38 supertasters are associated a lower risk of AD with the advancement of aging by mediating the variant-MGAM eQTL. With the longitudinal clinical and other biomarker data available through NACC, we are validating and further investigating the relationship.

3. Since NACC also provides the medication data for all the subjects, we are investigating if inhibition of MGAM expression could remediate the cognition decline in aging subjects. FDA approved MGAM inhibitors including acarbose and miglitol will be investigated for the purpose of precision drug repurposing for AD by comparing the drug taker and nontaker groups.

ADC have profiled >10,000 subjects' genetic data using different microarray platforms. We requesting the data to harmonize them for the purposing of precision drug repurposing, taking into account of different people's different genetic risk by leveraging the longitudinal data from NACC.