Interrogating the complex relationship between Alzheimer’s disease and blood pressure: two instrumental variable approaches to focus on pre-clinical stages of Alzheimer’s disease in UK Biobank

Background and Aims Evidence suggests there may be a bidirectional relationship between high blood pressure (BP) and Alzheimer’s disease (AD). It is hypothesised that this is due to cerebral changes during pre-clinical AD that cause elevation of systemic BP. We aimed to test this by exploring the effect of risk of pre-clinical AD on blood pressure.

We used data from the UK Biobank, including adults without prevalent or incident (within first 5-years of follow-up) clinical AD (N = 501,420, mean age 56.6, SD 8 years). We used two instrumental variables, an age-weighted parental dementia instrument score and a participant genetic instrument score, that are vulnerable to differing biases, to instrument risk of pre-clinical AD (the exposure). We tested the association of both instrument scores with systolic BP (SBP), diastolic BP (DBP) and hypertension. Sensitivity analyses were undertaken to explore different biases.

Both the higher parental dementia instrument and participant genetic instrument score were associated with higher mean SBP (difference in mean SBP mmHg per 1SD higher score: 0.12, 95% CI: 0.06 to 0.17, and 0.07, 95% CI: 0.00 to 0.13, respectively) but not DBP. Sensitivity analyses were largely consistent with these findings.

Our findings provide preliminary evidence that pre-clinical AD increases SBP. Further research is required to determine whether this increase in SBP is due to increased cerebrovascular resistance in pre-clinical AD. Obtaining a better understanding of the changing relationship with BP at different stages of AD may enable effective optimisation and targeting of therapies. Competing Interest Statement The authors have declared no competing interest. Clinical Protocols https://doi.org/10.17605/OSF.IO/5CJH6 Funding Statement JCP, EA and DAL were supported by a British Heart Foundation accelerator award (AA/18/7/34219). JCP, DA and DAL worked in a unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_00032/05). DAL's contribution is supported by her British Heart Foundation Chair (CH/F/20/90003). 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 study used deidentified data, which does not require additional ethics committee approval. 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 All data produced in the present work are contained in the manuscript