Assessing the repurposing potential of disease-modifying antirheumatic drug targets to reduce Alzheimer’s disease risk: a pQTL-based Mendelian randomization and colocalization analysis
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Background
Current literature has implicated systemic inflammation in the pathogenesis of Alzheimer’s 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.
Methods
We 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 Alzheimer’s Project ( n cases = 21,982, n controls = 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.
Results
Our 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 (H 3 = 46.5%).
Conclusions
Our 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.
