# Genetic associations of plasma proteomics with dementia subtypes and neuroimaging markers

## TL;DR

This study links plasma proteins to dementia and brain imaging traits, identifying both known and new proteins involved in dementia processes.

## Contribution

Novel proteins and pathways linked to dementia subtypes and neuroimaging markers using Mendelian randomization.

## Key findings

- Apolipoprotein E and other proteins showed protective associations across dementia subtypes.
- New proteins like butyrophilin subfamily 3 member A2 were identified as dementia-associated.
- Immune, metabolic, and vascular pathways were implicated in dementia etiology.

## Abstract

Dementia 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.

This 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).

Multiple 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.

The 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.

We 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.

We 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.