Authors: Joni V. Lindbohm, Nina Mars, Pyry N. Sipilä, Archana Singh-Manoux, Heiko Runz, , Gill Livingston, Sudha Seshadri, Ramnik Xavier, Aroon D. Hingorani, Samuli Ripatti, Mika Kivimäki
Published: 2022-10-14
DOI: 10.1038/s43587-022-00293-x
Source: Full article
AbstractImmune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88,P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.