Lisinopril and Cognitive Function: What the Evidence Actually Shows

Does lisinopril improve cognition or prevent dementia?

Lisinopril is approved for hypertension in adults and children 6 years and older, for systolic heart failure, and for reducing mortality in hemodynamically stable patients within 24 hours of acute myocardial infarction [2]. Cognition and dementia are not labeled indications [2].

The human evidence on this page is limited. One small 1-year pilot tested cognitive function, not dementia prevention, and one observational cohort grouped ACE inhibitors together rather than reporting lisinopril alone.

The direct trial: lisinopril versus candesartan

A double-blind pilot randomized 53 adults aged 60 and older with hypertension and executive dysfunction to lisinopril, candesartan, or hydrochlorothiazide for 1 year [1]. Of the 53, 47 had successful transcranial Doppler insonation [1].

On Trail Making Test Part B, an executive-function test, the candesartan group improved by 17.1 seconds, the hydrochlorothiazide group improved by 4.2 seconds, and the lisinopril group worsened by 14.4 seconds (P=0.008) [1]. Cerebral blood flow velocity tended to rise with candesartan and fall with lisinopril and hydrochlorothiazide, but the between-group difference was not significant (P=0.57); in participants with low baseline flow velocity, the between-group difference was significant (P=0.03) [1]. Carbon dioxide vasoreactivity and vasomotor range declined significantly within the lisinopril group (P=0.001 and P=0.02) but not the candesartan group, although the between-group differences were not significant (P=0.30 and P=0.46) [1].

The authors concluded that ARBs may preferentially preserve cerebral hemodynamics and executive function in people with executive dysfunction, and they called for a larger trial [1].

What the cohort data show

The Cardiovascular Health Study Cognition Substudy followed 1,054 adults with treated hypertension and no diagnosis of congestive heart failure, mean age 75, for a median of 6 years [3]. There were 414 participants exposed to ACE inhibitors and 640 not exposed, with 158 incident dementia cases [3].

Compared with other antihypertensive drugs, ACE inhibitors as a class were not associated with dementia risk (hazard ratio 1.01, 95% CI 0.88-1.15) or with a difference in 3MSE scores (-0.32 points per year, P=0.15) [3]. Centrally active ACE inhibitors as a group were associated with 65% less decline in 3MSE scores per year of exposure (P=0.01) [3]. Noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted hazard ratio 1.20, 95% CI 1.00-1.43 per year of exposure) and greater odds of disability in instrumental activities of daily living (adjusted odds ratio 1.16, 95% CI 1.03-1.30 per year of exposure) [3].

The analysis grouped ACE inhibitors as a class and by central activity [3]. It is observational, so it cannot separate a drug effect from differences in the people who received each drug.

Does the label list cognitive or psychiatric effects?

The lisinopril tablet label lists mood alterations, including depressive symptoms, mental confusion, and hallucinations under postmarketing nervous system and psychiatric disorders [2]. These are voluntary reports, and the label says frequency cannot be reliably estimated [2].

The same label warns about symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure, or death [2]. It names cerebrovascular disease among conditions that raise the risk of excessive hypotension and says to follow those patients closely for the first two weeks of treatment and after dose increases [2].