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. Methods 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. Results 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. Conclusions 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.