article · Scientific Reports
A prospective study of 66,610 matched adults aged 45 and older evaluated whether blood-brain barrier crossing antihypertensive medications reduce the risk of dementia compared to non-crossing alternatives. Over an average follow-up of nearly 12 years, individuals prescribed blood-brain barrier crossing drugs showed a 16 percent lower risk of new-onset dementia, a 17 percent reduction in all-cause mortality, and a 15 percent lower risk of dementia-related mortality. These associations remained robust across male and female subgroups and in sensitivity analyses accounting for competing mortality risks. Among specific drug classes, only blood-brain barrier crossing angiotensin II receptor blockers and beta-blockers exhibited statistically significant protective associations against dementia. The evidence suggests that blood-brain barrier permeability is a clinically relevant property in blood pressure treatments that may help prevent dementia, highlighting the need for validation through future randomised controlled trials.
Hypertension is common in ageing populations, and dementia represents a major public health challenge with limited preventive therapies. Recognising that blood pressure medications capable of entering the brain may offer greater neurological protection allows clinicians and researchers to consider drug pharmacokinetic properties when managing hypertension in older adults, potentially preserving cognitive function alongside cardiovascular health.
This observational research identifies opportunities for pharmaceutical developers and healthcare providers to prioritise blood-brain barrier permeability in cardiovascular drug selection and repurposing. Because the findings evaluate existing, approved medications, the insights could inform near-term clinical prescribing practices and drug development priorities. However, commercial or clinical translation remains at an intermediate stage that requires definitive validation through prospective randomised controlled trials.
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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.
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DOI: 10.1038/s41598-026-68950-4
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