Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases

Abstract

Immune 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.

Hospital-Diagnosed Infections, Autoimmune Diseases, and Subsequent Dementia Incidence

“…In most cases, autoimmune diseases are treated with longterm anti-inflammatory or immunosuppressive medications. This may mean that the small IRRs observed in our study are masked by the effect of medications either by suppressing severe inflammation (hence, inflammation per se was not assessed in our study) or reducing dementia risk, as suggested in some studies 34,37,38 (albeit with inconclusive evidence). To acknowledge this, we…”

“…Other limitations common to observational and registry-based studies include residual confounding from lifestyle differences and validity of diagnostic codes. We also did not have genetic data, which are likely to play an important role in the associations under investigation . Furthermore, it is not possible to conclude whether the dose-response association is present in both the short and long term, because we assessed this regardless of the timing.…”

“…6 Similar mechanisms involving peripheral systemic inflammation have also been hypothesized to link some autoimmune diseases with dementia. 7,29 Recent data from genomewide association studies 34 suggest that autoimmunity may be associated with dementia pathology. Overall, it is increasingly suggested that immune system dysregulation leading to an overactive, underactive, and/or chronic inflammatory response may play a role in the development of dementia.…”

“…We also did not have genetic data, which are likely to play an important role in the associations under investigation. 34 Furthermore, it is not possible to conclude whether the dose-response association is present in both the short and long term, because we assessed this regardless of the timing.…”

A FinnGen pilot clinical recall study for Alzheimer’s disease

“…The more than 11,000 FG participants with a probable diagnosis AD at start of our study represent about 8% of prevalent dementia and AD cases in Finland (20). As a research cohort, these individuals already contributed to improve the understanding of the genetic etiology of AD (27,28). Utilizing research data from this cohort for a clinical recall study required thorough collaboration between the study investigators and BEF over a period of nearly two years from first contact to study completion.…”