Causal relationships between plasma proteins and Alzheimer’s disease using bidirectional Mendelian randomization

J Alzheimers Dis. 2025 May 21:13872877251345151. doi: 10.1177/13872877251345151. Online ahead of print.

ABSTRACT

BackgroundAlzheimer’s disease (AD) is influenced by a complex interplay of genetic, immune, and metabolic factors. Identifying plasma proteins causally linked to AD could help clarify these pathways and uncover potential therapeutic targets.ObjectiveThis study aims to investigate the causal relationships between AD and plasma proteins.MethodsWe conducted a two-stage, two-sample Mendelian randomization (MR) analysis to explore the causal relationships between plasma protein levels and AD risk. In both stages, we used non-overlapping genome-wide association study datasets for exposures (plasma protein levels) and outcome (AD) to ensure robust and independent analyses. We examined both forward (from plasma proteins to AD risk) and reverse (from AD to plasma protein expression) causal effects to elucidate potential bidirectional relationships.ResultsOur MR analysis identified 25 plasma proteins with causal associations to AD, with many implicated in immune and lipid metabolic pathways. These findings reinforce the roles of inflammation and lipid metabolism in AD pathogenesis and offer novel insights into specific proteins that may serve as biomarkers or therapeutic targets.ConclusionsThis study provides further support for the relationship between immune and lipid metabolic dysregulation and AD, advancing our understanding of the molecular mechanisms underlying disease progression and highlighting key proteins for future research and therapeutic development.

PMID:40397384 | DOI:10.1177/13872877251345151