Burden of dementia following stroke subtypes: a study integrating the GBD database and Mendelian randomization.

Background: A large number of studies have previously established a causal association between stroke and dementia, and have demonstrated a strong correlation between ischemic or hemorrhagic stroke and all-cause dementia, respectively. Given the overall increasing prevalence of all-cause dementia worldwide and the absence of data from randomized clinical trials confirming the existence of effective dementia interventions.The aim of this paper is to apply the GBD database to estimate the proportion and trends of dementia following ischemic and hemorrhagic strokes globally and within regions, and to discuss potential risk factors for vascular dementia using Mendelian randomization (MR).

Methods: Using a literature review and Bayesian regression analysis, we estimated the relative risk of dementia following ischemic and hemorrhagic stroke. The proportion of dementia attributable to cerebral infarction and cerebral hemorrhage (PAF) and the burden of dementia under specific clinical etiology-year-sex-region were then calculated in conjunction with the Global Burden of Disease Study (GBD) burden of disease data. And projections were made for the next 10 years. Using the GWAS database, data on vascular dementia and 17 risk factors were collected, and causality was determined by two-sample MR analysis. In addition, potential mediators of risk factor effects on vascular dementia were searched from 338 cerebrospinal fluid metabolites by two-step MR.

Results: The relative risk of dementia following cerebral hemorrhage ( relative risk(RR):3.02[1.17-7.78],P<0.001 ) was higher than that of cerebral infarction (RR: 2.07[1.47-2.96], P<0.001). However, due to the high prevalence of cerebral infarction, the PAF for dementia due to cerebral infarction was higher than that of cerebral hemorrhage. Together, they explain 1.31% (1.41%-1.21%) of global dementia. The burden of dementia following both cerebral infarction and cerebral hemorrhage showed significant spatial and temporal heterogeneity. Four causal associations were replicated in two-sample MR and a mediating role for cerebrospinal fluid(CSF) metabolites X-11261 was identified by 2-step MR.

Interpretation: one point three one percent of dementia prevalence globally could be explained by ischemic stroke and hemorrhagic stroke.Quantifying the proportion of dementia caused by these two conditions has helped us to gain a comprehensive understanding of the causes of dementia.Through two-sample MR study and two-step MR analysis, modifiable risk factors and cerebrospinal fluid mediators associated with vascular dementia were identified, elucidating intervention methods for preventing or delaying the typical characteristics of dementia. This is crucial for future efforts in disease prevention and treatment.