Hypertension and Dementia: A Mendelian Randomisation Study Assessing Potential Causal Relationships with All-Cause Dementia, Alzheimer’s Disease and Vascular Dementia in the UK Biobank

Abstract Hypertension is a key modifiable risk factor for longevity. However, evidence linking hypertension to dementia remains inconsistent, potentially due to subtype-specific effects. We aimed to examine relationships between systolic blood pressure (SBP) and risk of Alzheimer’s disease (AD) and vascular dementia (VaD) using individual-level Mendelian randomization (MR) analyses. Logistic and Cox regressions assessed the association of blood pressure traits with all-cause dementia, AD and VaD in the UK Biobank cohort. Observational analyses indicated SBP was associated with increased risk of all dementia outcomes. MR analyses indicated genetically proxied SBP was associated with increased risk of all-cause dementia (OR=1.26, [95% CI:1.15;1.38]; HR=1.28, [95% CI:1.17;1.40]). When stratified by subtype, higher SBP was associated with increased risk of VaD (OR=1.56, [95% CI:1.25;1.93]; HR=1.58, [95% CI:1.28;1.97]), but not AD (OR=1.10, [95% CI:0.95;1.26]; HR=1.11, [95% CI:0.97;1.28]). Post-hoc analyses supported a differential effect. Hypertension appears to be a greater risk factor for VaD than AD. Competing Interest Statement The authors have declared no competing interest. Funding Statement The United Kingdom Research and Innovation Medical Research Council. UK Dementia Research Institute Molecular Epidemiology and Causal Inference which receives its funding from UK DRI Ltd, funded by the UK MRC AS and ARUK. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The present analyses were conducted under the UK Biobank Application No. 69328 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Data is available via the UK Biobank. Analytic code will be available via GitHub on publication of the manuscript in a peer reviewed journal.