Mendelian Randomization: Blood Pressure in Midlife and Risk of Late-Onset Alzheimer's Disease

Late-onset Alzheimer’s disease (LOAD) is a major public health concern with no cure or disease modifying treatment. Due to a large ageing population and expected increases in prevalence and incidence worldwide, identifying preventive interventions for LOAD are critically important. High blood pressure in midlife is considered a significant modifiable risk factor for LOAD. We used Mendelian Randomization with genetic instruments associated with blood pressure during midlife to assess an association of elevated blood pressure on LOAD. We also conducted sensitivity analyses to control for confounding and bias by BMI. In main analyses, we found a consistent null association of midlife elevated blood pressure with LOAD. In sensitivity analyses accounting for possible invalid genetic instruments, we found that higher genetically predicted SBP was associated with lower LOAD risk (OR per 16.6 mmHg of SBP: 0.97 (0.94-0.99); p = 0.02) and higher DBP was associated with lower LOAD risk (OR per 10.9 mmHg of DBP: 0.96 (0.93-0.99); p = 0.02). However, these findings are potentially influenced by confounding from anti-hypertensive medication use or survival bias. In addition, we found no major confounding or bias from BMI for the effect of blood pressure on LOAD. Although the findings in this study found no positive association between elevated blood pressure and LOAD, future studies that focus on clinical thresholds or uncontrolled high blood pressure may provide further insight.Release after 01/01/202