Impact of Different Antihypertensive Drug Classes on Incident Dementia in Older Adults: A Systematic Review and Meta-Analysis.

OBJECTIVES

To evaluate the association between different classes of antihypertensive medications (AHMs) and dementia risk in older adults through systematic review and meta-analysis.

DESIGN

Systematic review and exploratory network meta-analysis (NMA) following PRISMA-MOOSE guidelines. For traditional meta-analysis, random-effects models (DerSimonian-Laird method) were used for dichotomous outcomes, and fixed-effects models for continuous outcomes. Exploratory NMA employed a frequentist fixed-effects model (Stata 18 network package), as the sparse network precluded Bayesian estimation.

SETTING AND

PARTICIPANTS

Four multicenter randomized controlled trials [Syst-Eur, Perindopril Protection Against Recurrent Stroke Study (PROGRESS), SCOPE, HYVET-COG] comprising 16,823 hypertensive older adults without dementia at baseline, with follow-up durations of 2.0-3.9 years.

METHODS

Literature searches were conducted in PubMed, Cochrane Library, Web of Science, and Embase from inception to December 31, 2025. Risk of bias was assessed using Cochrane RoB 2, and evidence certainty was evaluated using GRADE. Random-effects models pooled dichotomous outcomes [odds ratios (OR)] and fixed-effects models analyzed continuous outcomes [standardized mean differences (SMDs)].

RESULTS

Antihypertensive treatment significantly improved cognitive function scores (SMD, 0.06; 95% CI, 0.03-0.09; P < .001, GRADE moderate certainty) and showed a nonsignificant trend toward reduced dementia incidence (OR, 0.89; 95% CI, 0.76-1.05; P = .172, GRADE low certainty). Exploratory NMA suggested calcium channel blockers ranked highest for dementia prevention [surface under the cumulative ranking curve (SUCRA) = 94.7%], while diuretic ± angiotensin-converting enzyme inhibitor combinations ranked highest for cognitive improvement (SUCRA = 95.3%); however, rankings were highly uncertain due to network sparsity (one study per node).

CONCLUSIONS AND IMPLICATIONS: Antihypertensive therapy significantly improves cognitive function with moderate certainty evidence, supporting its use for cognitive protection in older adults with hypertension. The trend toward dementia risk reduction, although uncertain, suggests potential long-term benefits warranting further investigation.

CLINICAL IMPLICATIONS: These findings support optimizing antihypertensive regimens for dementia prevention in high-risk populations, with drug class selection informed by specific treatment goals (dementia prevention vs cognitive maintenance).

POLICY AND RESEARCH IMPLICATIONS: Current evidence is limited by few studies and short follow-up; large-scale randomized controlled trials with dementia as a primary endpoint, head-to-head drug class comparisons, and inclusion of long-term care residents-who bear the highest disease burden yet are underrepresented in trials-are urgently needed to inform precision prescribing guidelines.