Angiotensin-II stimulating agents associated with lower burden of key AD neuropathologies

Cumulative angiotensin II–stimulating (vs angiotensin II–inhibiting) antihypertensive exposure is associated with lower risk of certain dementia-related neuropathologies, a US study has found.

The study, a first investigating angiotensin II–stimulating vs angiotensin II–inhibiting antihypertensive medications in a community-based autopsy cohort with a broad range of neuropathological outcomes, included 756 participants (mean age at death, 89.2 years; women, 58.2 percent; White. 93.9 percent; mean follow-up period, 22.2 years) enrolled from the Adult Changes in Thought (ACT) cohort. The study was conducted at Kaiser Permanente Washington between February 1994 and November 2022.  Participants had blood pressure (BP) measurements and at least 1 person-year (PY) of angiotensin II–stimulating or –inhibiting antihypertensive medication exposure prior to death. [JAMA Open 2026;9: e2559113]

Most participants (77.2 percent) had exposure to angiotensin II–simulating antihypertensives. An even higher proportion (93.4 percent) had exposure to an angiotensin II–inhibiting antihypertensives. A majority of participants (70.6 percent) used both types of antihypertensives, while 2.8 percent used exclusively angiotensin II–inhibiting antihypertensives and 6.6 percent, exclusively angiotensin II–stimulating antihypertensives. Thiazides accounted for the highest proportion (68.4 percent) of PYs for stimulating regimens, and β-blockers accounted for the highest proportion (53.9 percent) of PYs for inhibiting regimens.

Findings revealed a 6 percent lower risk of arteriolosclerosis (relative risk [RR], 0.94; 95 percent confidence interval [CI], 0.89–0.99) associated with exposure to five additional PYs of angiotensin II–stimulating antihypertensives vs exposure to five additional PYs of angiotensin II–inhibiting antihypertensives, with long-term use (≥15 years) associated with a 24 percent lower risk (RR, 0.76; 95 percent CI, 0.63–0.91).  

Exposure to five additional PYs of angiotensin II–stimulating antihypertensives was also associated with a non-statistically significant lower risk (5–6 percent) of Alzheimer’s disease neuropathology (Braak stage V or VI; Consortium to Establish a Registry for Alzheimer Disease [CERAD] level, moderate or frequent; Alzheimer Disease Neuropathologic Change [ADNC] score, intermediate or high), an 11 percent lower risk of limbic-predominant age-related TDP-43 encephalopathy (LATE; stage 2–3 pathology), and a 16 percent lower risk of Lewy bodies in the neocortex.

For exploratory neuropathology outcomes, while there were no differences between angiotensin II regimen types and quantitative measures of  Aβ42, exposure to five additional PYs of angiotensin II–stimulating antihypertensives was associated with 21 percent less phosphorylated tau burden in the temporal lobe, 17 percent less in the hippocampus, 14 percent less in the cornu ammonis subfield 1, and 17 percent less in the transentorhinal cortex.

The authors noted that a major strength of the study was the extensive longitudinal BP data, allowing adjustments throughout the exposure period (vs prior neuropathology studies which did not adjust for BP or adjusted for BP over a short follow-up time). However, the angiotensin hypothesis, which represented only a single mechanistic framework, was a limitation of the study, as other cellular pathways may underlie the observed associations. Furthermore, the study population was predominantly White and well-educated, which may limit generalizability.