Immune system and blood-brain barrier-wide biomarker analyses provide causal evidence for autoimmunity in dementia

Abstract

AbstractImmune system and blood brain barrier (BBB) dysfunction are implicated in the development of Alzheimer’s disease and other dementias, but their causal role remains unknown. We performed Mendelian randomization (MR) for over 43,643 immune system and BBB-related biomarkers and identified 126 potential causal risk factors for dementias. A phenome-wide analysis using MR-based polygenic risk score in FinnGen study (N=339,233) for these risk factors revealed a common genetic background for dementias and autoimmune diseases which was supported by further HLA analyses. Pathway analyses linked the 126 proteins to amyloid-β, tau and α-synuclein pathways, increased inflammatory responses, and altered self-tolerance mechanisms. In inverse-probability-weighted analyses simulating randomized controlled drug trials in observational data, anti-inflammatory and immunosuppressive medications were associated with reduced dementia risk (p<0.01 for methotrexate and TNF-α inhibitors). These converging results from different research lines suggest that autoimmunity is a modifiable component in diseases causing dementia.