Journal-based CME Course: Angiotensin II–Stimulating Antihypertensive Medications and Dementia-Related Neuropathology

Activity ID

14923

Expires

March 24, 2029

Format Type

Journal-based

CME Credit

1

Fee

$30

CME Provider: JAMA Network Open

Description of CME Course

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.

Disclaimers

1. This activity is accredited by the American Medical Association.
2. This activity is free to AMA members.

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