IntroductionDementia is a rising global health challenge. Advances in large-scale proteomics and genetic databases have enabled high-throughput screening approaches to uncover novel mechanistic pathways and therapeutic targets.MethodsThis study used a Mendelian randomization framework to examine genetic associations of 2172 plasma proteins (UK Biobank, n = 54,219) with: (1) dementia subtypes (FinnGen, n = 429,209), including Alzheimer's disease (n = 12,348), vascular dementia (n = 2667), and Parkinson's disease dementia (n = 589); and (2) global neuroimaging markers (UK Biobank), including white matter hyperintensities (n = 42,310), fractional anisotropy (n = 17,663), and mean diffusivity (n = 17,467).ResultMultiple potential causal protein-outcome relationships were identified, corroborating known associations (e.g., apolipoprotein E, synaptosomal-associated protein 25) and uncovering more novel proteins (e.g., butyrophilin subfamily 3 member A2, granzyme A, contactin-2, and trefoil factor 3) potentially involved in dementia disease processes.DiscussionThe identified proteins have diverse functions spanning immune regulation, cellular proliferation, neuronal stability, and neuroinflammation. The findings increase our understanding of disease processes governing cognitive health and highlight candidate proteins with potential as new disease biomarkers or therapeutic targets.HighlightsWe used Mendelian randomization to link 2172 plasma proteins to dementia and brain imaging traits.Apolipoprotein E, triggering receptor expressed on myeloid cells 2, and Fc receptor-like 3 showed protective associations across dementia subtypes.Butyrophilin subfamily 3 member A2, granzyme A, contactin-2, and trefoil factor 3 were uncovered as novel dementia-associated proteins.Immune, metabolic, and vascular pathways were implicated in the etiology of dementia.