Angiotensin-Converting Enzyme Inhibitors and Cognitive Decline in Older Adults With Hypertension: Results From the Cardiovascular Health Study | Dementia and Cognitive Impairment | JAMA Internal Medicine | JAMA Network
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Original Investigation
July 13, 2009

Angiotensin-Converting Enzyme Inhibitors and Cognitive Decline in Older Adults With Hypertension: Results From the Cardiovascular Health Study

Author Affiliations

Author Affiliations: Sticht Center on Aging, Wake Forest University, Winston-Salem, North Carolina (Drs Sink, Leng, Williamson, Kritchevsky, Atkinson, Robbins, and Goff); Departments of Neurology and Psychiatry, University of California, San Francisco (Dr Yaffe); Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Kuller); Division of Geriatric Medicine, The Johns Hopkins University, Baltimore, Maryland (Dr Yasar); and Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle (Dr Psaty).Group Information: A list of the principal investigators and institutions of the Cardiovascular Health Study can be found at

Arch Intern Med. 2009;169(13):1195-1202. doi:10.1001/archinternmed.2009.175

Background  Hypertension (HTN) is a risk factor for dementia, and animal studies suggest that centrally active angiotensin-converting enzyme (ACE) inhibitors (those that cross the blood-brain barrier) may protect against dementia beyond HTN control.

Methods  Participants in the Cardiovascular Health Study Cognition Substudy with treated HTN and no diagnosis of congestive heart failure (n = 1054; mean age, 75 years) were followed up for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared with other anti-HTN agents, was associated with a lower risk of incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs).

Results  Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia. Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.88-1.15), difference in 3MSE scores (−0.32 points per year; P = .15), or odds of disability in IADLs (odds ratio [OR], 1.06; 95% CI, 0.99-1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (P = .01), and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20; 95% CI, 1.00-1.43 per year of exposure) and greater odds of disability in IADLs (adjusted OR, 1.16; 95% CI, 1.03-1.30 per year of exposure) compared with other anti-HTN drugs.

Conclusions  While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within-class differences in regard to these outcomes. These results should be confirmed with a randomized clinical trial of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.