Immune-mediated diseases are associated with a higher incidence of dementia: a prospective cohort study of 375,894 individuals

Background Immune system dysregulation plays a vital role in the pathogenesis of neurodegenerative diseases, even considered to be as important as classical pathological protein aggregation assumption. However, the associations of immune-mediated diseases with incident dementia are unclear and need to be clarified in prospective studies with a large population and long follow-up time. Methods We investigated the relationship between any or individual immune-mediated diseases and incident dementia based on a prospective cohort UK Biobank. The risk for dementia was assessed with multivariable hazard ratio (HR) and 95% confidence interval (CI) after adjusting for various potential confounders using time-varying Cox proportional hazards regression. We also performed the subgroup Cox analysis stratified by time since immune-mediated diseases and gender. Causal mediation analyses with 1000 bootstrapped iterations were conducted to explore the mediation effects of peripheral immune cells on the associations of immune-mediated diseases with dementia. Results A total of 375,894 participants were included in the study, among which 5291 developed dementia during a median follow-up of 9.08 years. Immune-mediated diseases were associated with an increased risk of dementia (HR, 1.10; 95% CI, 1.00-1.21), and the risk was highest between 1 and 2 years after immune-mediated diseases onset (HR, 2.74; 95% CI, 1.86-4.04). Females who suffered from immune-mediated diseases were more prone to AD, while males were more susceptible to VD. Four of the individual immune-mediated diseases including type I diabetes mellitus (HR, 2.49; 95% CI, 1.97-3.15), rheumatic fever or rheumatic heart diseases (HR, 1.36; 95% CI, 1.05-1.77), multiple sclerosis (HR, 2.87; 95% CI, 1.92-4.30), and necrotizing vasculopathies (HR, 1.71; 95%CI, 1.03-2.85) were significantly related to higher dementia incidence. The relationship between immune-mediated diseases and dementia was partially mediated by peripheral immune cells including neutrophils and lymphocytes. Conclusions In this large cohort study, immune-mediated diseases were proven to be significantly associated with an increased risk of incident dementia, especially for type I diabetes mellitus which was observed to be related to the higher incidence of all types of dementia. Our findings could provide new sights on dementia pathogenesis and intervention from the perspective of systemic immunology and immune-mediated diseases.