ArticleAmerican journal of cardiovascular disease2026
Mid-life antihypertensive initiation and incident dementia: a machine learning-weighted target trial emulation in the health and retirement study.
Article in American journal of cardiovascular disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMid-life hypertension is a treatable vascular risk for dementia, yet trial evidence on whether starting antihypertensives in middle age lowers late-life dementia remains mixed. This study aimed to emulate a randomized trial to estimate whether initiating antihypertensive therapy at mid-life reduces subsequent dementia risk.
methodsWe emulated a randomized target trial of antihypertensive initiation using Health and Retirement Study data (2002-2020; 18-year follow-up). Eligible adults aged 45-65 with incident hypertension and dementia-free at baseline (n = 2,491) were classified in 2002 as antihypertensive treatment initiators or non-initiators. Inverse probability weights combined (I) a Firth-penalized logistic model for treatment initiation and (II) biennial censoring models; weighted Cox regression estimated hazard ratios (HRs) for incident dementia. To probe model dependence, we re-estimated treatment weights with a Super Learner ensemble and repeated all analyses.
resultsGroups differed on several baseline covariates, but weighting brought every standardized mean difference to <0.10. During follow-up, cumulative dementia incidence reached 15% in non-initiators and 13% in initiators. The intention-to-treat risk ratio (RR) was 0.89 (95% confidence interval [CI], 0.57-1.62); biennial RRs were likewise close to the null. Re-estimating treatment weights with a Super Learner ensemble yielded comparable covariate balance and a year-18 RR of 1.05 (0.74-1.70), essentially reproducing the primary result. Analyses accounting for competing risks of death or dropout did not materially change the estimates.
conclusionsIn this nationally representative cohort, starting antihypertensive therapy in mid-life did not meaningfully change dementia risk across 18 years. Agreement between conventional and machine-learning propensity approaches makes a large protective or harmful effect unlikely and underscores the need to explore additional strategies for dementia prevention beyond routine blood pressure pharmacotherapy.
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