Combining GWAS Summary Data and Proteomics Identified Potential Drug Targets in Dementia

Due to progressive cognitive loss and subsequent incapability of daily life, the development of novel therapeutics is urgently needed for dementia patients. We performed a two-sample bi-directional Mendelian randomization (MR) analysis using summary-level statistics to identify causality between peripheral and cerebrospinal fluid (CSF) proteins and the risk of dementia. Genetic variants were subtracted from the Genome-Wide Association Studies (GWAS) results. Wald ratio (WR) and inverse-variance weighted (IVW) ratio were utilized to estimate the causal effects of plasma and CSF proteins on dementia. Reverse MR, Steiger filtering, Bayesian co-localization phenotype scanning, and external validation were integrated to strengthen the robustness of primary MR results. After sensitivity analysis, six circulating proteins were identified in three dementia classifications, whereas no causality was found in frontotemporal dementia (FTD). Elevated levels of circulating C1R protein increased the odds of developing Alzheimer's disease (AD), while PILRA and CELA2A were estimated to protect against the pathogenesis of AD; genetically predicted increase of α-synuclein and APOE elevated the occurrence of Dementia of Lewy Bodies (DLB); elevated level of circulating CRP was assessed to increase the onset of vascular dementia (VD). Our MR analyses identified a genetically predicted association between circulating C1R, PILRA, and CELA2A and the risk of AD, causal estimates between α-syn, APOE protein, and the onset of DLB, and a robust correlation between CRP and the etiology of VD. This study might guide the discovery of disease etiology and build up a novel disease-modifying paradigm of dementia.