# Angiotensin II–Stimulating Antihypertensive Medications and Dementia-Related Neuropathology

## TL;DR

This study found that antihypertensive medications stimulating angiotensin II receptors may reduce dementia-related brain damage compared to those that inhibit these receptors.

## Contribution

The study reveals a novel association between angiotensin II–stimulating medications and reduced neuropathology risk beyond blood pressure effects.

## Key findings

- Long-term use of angiotensin II–stimulating medications was linked to a 24% lower risk of arteriolosclerosis.
- These medications were associated with reduced phosphorylated tau burden in key brain regions.
- No significant effect on Aβ42 levels was observed.

## Abstract

Are antihypertensive medications that stimulate vs inhibit angiotensin II type 2 or 4 receptors associated with lower risk for neuropathology burden beyond blood pressure control?

In this cohort study with 756 decedents, cumulative angiotensin II–stimulating exposure was associated with lower risk for some types of neuropathology relative to angiotensin II–inhibiting exposure. Long-term angiotensin II–stimulating exposure (≥15 years) was associated with a 24% lower risk for arteriolosclerosis.

This study suggests that, relative to angiotensin II–inhibiting antihypertensive exposure, angiotensin II–stimulating antihypertensive medications were associated with lower risk of certain dementia-related neuropathologies.

Antihypertensive medications that stimulate angiotensin II type 2 or 4 receptors (angiotensin II–stimulating medications) may be associated with lower risk of dementia.

To examine associations between cumulative exposure to angiotensin II–stimulating vs angiotensin II–inhibiting antihypertensive medications and neuropathology, accounting for blood pressure.

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.

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).

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.

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.

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.

This cohort study examines associations between cumulative exposure to angiotensin II–stimulating vs angiotensin II–inhibiting antihypertensive medications and neuropathology beyond blood pressure control.