The Use of Antihypertensive Medication and In Vivo Alzheimer's Disease Pathology

Abstract

Objective: We investigated whether the use of antihypertensive medication (AHM) is associated with in vivo Alzheimer's Disease (AD) pathologies in older adults with hypertension and examined if the effect differs by drug-class and blood-brain barrier (BBB) permeability of the drug.

Methods: This cross-sectional study recruited participants from the Korean Brain Aging Study for the Early Diagnosis and Prevention of Alzheimer's Disease. Participants comprised both cognitively normal and impaired older adults diagnosed with hypertension (n = 408). All participants underwent comprehensive clinical assessment and [¹¹C] Pittsburgh Compound B positron emission tomography (PET) for measurement of cerebral β-amyloid (Aβ) deposition. Additionally, a subset of participants (n = 120) was subjected to [¹⁸F] AV-1451 PET to assess tau deposition.

Results: The AHM group (n = 227) exhibited significantly lower Aβ deposition (B [SE] = -0.104 [0.037], p = 0.006) compared to the non-AHM group (n = 181), even after controlling for age, sex, apolipoprotein E ε4-positivity, vascular risk factors, and mean arterial blood pressure. Further analysis by AHM class showed an association between the use of renin-angiotensin system inhibitors (RASi) and less Aβ deposition (B [SE] = -0.143[0.049], p = 0.004). No significant relationships were observed between the use of BBB-permeable AHM and Aβ deposition. Additionally, associations between AHM use and tau deposition did not reach statistical significance.

Interpretation: Our findings suggest that AHM use may be associated with lower Aβ burden in older adults with hypertension. Further studies exploring the underlying mechanism, particularly related to RASi, may provide insights into new therapeutic targets for AD. ANN NEUROL 2025;97:1051-1061.

FIGURE 1:

Comparison of global Aβ retention between AHM users and non-users among hypertensive older adults. The estimated mean and 95% confidence interval of global Aβ deposition in the AHM and non-AHM groups, obtained from a multiple linear regression analysis before IPTW adjustment (blue) and from an IPTW-adjusted regression analysis (red), are presented. Aβ = Beta-amyloid; AHM = antihypertensive medication; APOE4 = apolipoprotein E ε4 allele; IPTW = inverse probability of treatment weighting; MAP = mean arterial pressure; SUVr = standardized uptake value ratio; VRS = vascular risk factor composite score.

FIGURE 2:

AHM class-specific comparison of global Aβ retention between users and non-users of (A) RAS inhibitors, (B) beta-blockers, (C) calcium channel blockers, and (D) diuretics. The estimated mean and 95% confidence interval of global Aβ deposition in the users and non-users of each AHM class, obtained from multiple linear regression analyses before IPTW adjustment (blue) and from IPTW-adjusted regression analyses (red), are presented. Aβ = beta-amyloid; AHM = antihypertensive medication; APOE4 = apolipoprotein E ε4 allele; IPTW = inverse probability of treatment weighting; MAP = mean arterial pressure; SUVr = standardized uptake value ratio; VRS = vascular risk factor composite score.

FIGURE 3:

Comparison of global Aβ retention between users and non-users of BBB-permeable AHM. The estimated mean and 95% confidence interval of global Aβ deposition in users and non-users of BBB-permeable AHM (BBB [right] and no BBB [left] groups, respectively), obtained from a multiple linear regression analysis before IPTW adjustment (blue) and from an IPTW-adjusted regression analysis (red), are presented. Aβ = beta-amyloid; AHM = antihypertensive medication; APOE4 = apolipoprotein E ε4 allele; IPTW = inverse probability of treatment weighting; MAP = mean arterial pressure; SUVr = standardized uptake value ratio; VRS = vascular risk factor composite score.