Assessing the repurposing potential of disease-modifying antirheumatic drug targets to reduce Alzheimer's disease risk: a pQTL-based Mendelian randomization and colocalization analysis

BackgroundCurrent literature has implicated systemic inflammation in the pathogenesis of Alzheimers disease (AD). However, the viability of anti-inflammatory drug targets as repurposed treatment candidates for AD remains unclear. We utilized two-sample Mendelian randomization (MR) and colocalization analysis to investigate whether disease-modifying antirheumatic drug (DMARD) targets reduce AD risk. MethodsWe investigated 9 DMARD targets, using blood protein quantitative trait loci (pQTLs) from the UK Biobank Pharma Proteomics Project (n = 54,219). The associations of these variants and AD were extracted from the International Genomics of Alzheimers Project (ncases = 21,982, ncontrols = 41,944). We used two-sample MR analyses to estimate the effects of perturbing DMARD targets on AD risk. We also examined the colocalization of target pQTLs and AD signals in the cis-regions of target-encoding genes. ResultsOur MR estimates suggested that a 1 SD increase in plasma protein concentration of the etanercept target, FCGR3B, increased the risk of AD by 10% (OR 1.10; 95% CI [1.02, 1.19]; p = 0.01). We found little evidence that the remaining DMARD targets reduced AD risk. Further colocalization analysis indicated no evidence of colocalization between encoding genes of DMARD targets and AD, including FCGR3B. Though, there was suggestive evidence of a non-colocalized association between TNF and AD on chromosome 6 via distinct causal variants (H3 = 46.5%). ConclusionsOur findings suggest that the majority of analyzed DMARD targets were unlikely to reduce AD risk, except for FCGR3B. Future research in AD drug targeting and repurposing should examine the therapeutic viability of drugs which lower FCGR3B protein levels in blood plasma.