Association between genetically proxied PPARG activation and early onset Alzheimer's disease: A drug target Mendelian randomization study.

BACKGROUND

Early-onset Alzheimer's disease (EOAD), which has an onset before the age of 65, is overshadowed by the more prevalent late-onset Alzheimer's disease (LOAD). Nevertheless, rather than being merely a form of LOAD that occurs at a prematurely defined younger age, EOAD differs from LOAD in multiple ways. Given these disparities, understanding the potential treatment options for EOAD becomes crucial.

OBJECTIVE

We aim to assess anti-diabetic drugs' potential utility in treating EOAD and LOAD from a novel perspective via drug-targeted Mendelian randomization (MR) analysis.

METHODS

Through Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis, we assessed the associations between anti-diabetic drug targets (including DPP-4 inhibitor, Thiazolidinedione, GLP1R agonist, Sulfonylureas, SLC5A2 inhibitor, and Insulin/Insulin analog) and AD outcomes (EOAD and LOAD). We utilized two types of genetic instruments to represent the exposure to anti-diabetic drugs: eQTLs of genes encoding drug target proteins and genetic variants within or near genes encoding these target proteins associated with HbA1c from genome-wide association studies.

RESULTS

SMR analysis showed that enhanced PPARG gene expression in the blood was a protective factor for EOAD (OR = 0.733, 95%CI = 0.548-0.979,  = 0.035). Additionally, an IVW-MR association was found between HbA1c mediated by PPARG and EOAD (OR = 0.295, 95%CI = 0.092-0.949,  = 0.041).

CONCLUSIONS

This study suggests that Thiazolidinedione therapy could help suppress the development of EOAD, supporting further exploration of PPARG-targeted anti-diabetic drug development.