Blood–brain barrier crossing of antihypertensives and risk of dementia: a comparative analysis

We aimed to investigate the dementia protective effects of blood-brain barrier (BBB)-crossing and non-crossing antihypertensive medications (AHMs). In this prospective study using the 45 and Up Study cohort, we included participants aged ≥ 45 years with hypertension who initiated either BBB-crossing or non-crossing AHMs between January 2004 and June 2022. They were followed from the index date until dementia diagnosis, death, or 30 June 2023. BBB-crossing AHM users were propensity matched (1:1) with non-crossing AHM users by age, sex, smoking status, and follow-up duration. Cox proportional hazards models estimated adjusted (by covariates including diet and physical activity) hazard ratios (HRs) for incident dementia, all-cause mortality, and dementia-related mortality. After matching, 66,610 participants were included (mean age [standard deviation (SD)] 66.9 [9.3] years; 53.2% women; mean follow-up 11.9 [5.3] years). Compared with non-BBB-crossing AHMs, use of BBB-crossing AHMs was associated with a lower risk of new-onset dementia (HR, 0.84; 95% CI 0.80–0.88), all-cause mortality (HR, 0.83; 95% CI 0.82–0.86), and dementia-related mortality (HR, 0.85; 95% CI 0.79–0.92). Subgroup analyses revealed a significant reduction in dementia risk for both females and males, with no significant sex interaction (p = 0.067). Based on the AHM class, only angiotensin II receptor blockers (HR, 0.89; 95% CI 0.80–0.99) and β-blockers (HR, 0.76; 95% CI 0.63–0.93) were found to significantly reduce the risk of dementia. With sensitivity analyses, the dementia-protective effect of BBB-crossing AHMs remained significant after excluding individuals with hypertension identified solely by AHM use (HR, 0.84; 95% CI 0.79–0.89) and when accounting for competing mortality risk (HR, 0.84; 95% CI 0.80–0.89). Use of BBB-crossing AHMs was associated with a reduced risk of dementia and mortality. Findings highlight BBB crossing as a potentially relevant pharmacokinetic property of AHMs influencing dementia prevention, warranting further investigation in randomised controlled trials.