Five additional person-years of angiotensin II–stimulating antihypertensives were linked to 6% lower arteriolosclerosis risk (RR 0.94) and 24% lower risk with ≥15 years use (RR 0.76).
Does cumulative exposure to angiotensin II-stimulating antihypertensive medications reduce dementia-related neuropathology compared to angiotensin II-inhibiting medications in older adults?
Cumulative use of angiotensin II-stimulating antihypertensives is associated with reduced neuropathological burden, including arteriolosclerosis and tau pathology, compared to angiotensin II-inhibiting agents.
Importance Antihypertensive medications that stimulate angiotensin II type 2 or 4 receptors (angiotensin II–stimulating medications) may be associated with lower risk of dementia. Objective To examine associations between cumulative exposure to angiotensin II–stimulating vs angiotensin II–inhibiting antihypertensive medications and neuropathology, accounting for blood pressure. Design, Setting, and Participants This community-based autopsy cohort study from the Adult Changes in Thought cohort was conducted at Kaiser Permanente Washington between February 24, 1994, and November 25, 2022, among 756 participants who had blood pressure measurements and at least 1 person-year (PY) of angiotensin II–stimulating or –inhibiting antihypertensive medication exposure prior to death. Statistical analysis was performed between September 2024 and August 2025. Exposure Angiotensin II–stimulating antihypertensive medications (angiotensin II receptor blockers, dihydropyridine calcium channel blockers, thiazides) and angiotensin II–inhibiting antihypertensive medications (angiotensin-converting enzyme inhibitors, β-blockers, nondihydropyridine calcium channel blockers) were ascertained from paper-based medical records (before 1977) and electronic prescription fill data (after 1977). The primary exposure was cumulative angiotensin II PYs, and the secondary exposure was long-term use (≥15 years). Main Outcomes and Measures Neuropathology outcomes were classified as Alzheimer disease related, vascular brain injury, or other. Exploratory outcomes included quantitative measures of Aβ42 and phosphorylated tau. Data were analyzed using multivariable modified Poisson, proportional odds, and linear regression models and accounted for potential selection bias. Results The sample included 756 participants (mean SD age at death, 89.2 6.4 years; 440 women 58.2%; mean SD follow-up, 22.2 13.5 years). Compared with exposure to 5 additional PYs of angiotensin II–inhibiting antihypertensive medications, exposure to 5 additional PYs of angiotensin II–stimulating antihypertensive medications was associated with a 6% lower risk for arteriolosclerosis (relative risk RR, 0.94; 95% CI, 0.89-0.99), with long-term use associated with a 24% lower risk (RR, 0.76; 95% CI, 0.63-0.91). For exploratory outcomes, PYs of angiotensin II–stimulating antihypertensive medications were associated with less quantitative phosphorylated tau burden in several brain regions (temporal lobe adjusted ratio of geometric means, 0.79; 95% CI, 0.62-1.00, hippocampus adjusted ratio of geometric means, 0.83; 95% CI, 0.71-0.97, cornu ammonis subfield 1 adjusted ratio of geometric means, 0.86; 95% CI, 0.74-0.99, and transentorhinal cortex adjusted ratio of geometric means, 0.83; 95% CI, 0.70-0.98) but not with Aβ42 quantitative measures. Conclusions and Relevance In this community-based autopsy cohort study, angiotensin II–stimulating antihypertensive medications were associated with lower risk of neuropathological burden, supporting findings from epidemiologic dementia studies. Additional mechanistic research examining the effects of individual antihypertensive classes on Alzheimer disease–related biomarkers is warranted.
Gray et al. (2026) studied this question. Five additional person-years of angiotensin II–stimulating antihypertensives were linked to 6% lower arteriolosclerosis risk (RR 0.94) and 24% lower risk with ≥15 years use (RR 0.76).