Centrally Active ACE Inhibitors Linked to Lower Rates of Mental Decline in Elderly

Laurie Barclay, MD

May 05, 2007

May 5, 2007 — Compared with other antihypertensive agents, centrally active angiotensin-converting enzyme inhibitors (ACEIs) are associated with slower rates of cognitive decline over 6 years in elderly people free of dementia at baseline, according to findings from the Cardiovascular Health Study (CHS) presented on May 5 at the annual meeting of the American Geriatrics Society in Seattle, Washington.

"ACE inhibitors that cross the blood-brain barrier reduce cognitive decline by 50% compared [with] the decline seen in people on other blood pressure medications," presenter and lead author Kaycee M. Sink, MD, MAS, an assistant professor of internal medicine in gerontology at Wake Forest University School of Medicine in Winston-Salem, North Carolina, told Medscape.

Centrally active ACEIs, such as captropril (Capoten), fosinopril (Monopril), lisinopril (Prinivil or Zestril), perindopril (Aceon), ramipril (Altace), and trandolapril (Mavik), cross the blood-brain barrier. Previous animal studies suggest that centrally active ACEIs protect against dementia not only by controlling hypertension, but also by decreasing oxidative stress and reducing inflammation in the brain.

"Treating blood pressure may be about more than just getting blood pressure to a certain target," Dr. Sink said. "Which drug we use may have implications beyond blood pressure control, like reducing risk of cognitive decline. High blood pressure is a risk factor for dementia, so it is important to know if the type of blood pressure medicine a person takes can cut that risk."

The CHS is a long-term study of cardiovascular risk factors that enrolled 5888 people older than 65 years of age from Forsyth County, North Carolina; Sacramento County, California; Pittsburgh, Pennsylvania; and Washington County, Maryland. Of the 1142 CHS participants with treated hypertension and no dementia at baseline, 68 had heart failure and were excluded. Median follow-up for this cohort was 6 years; 20 participants were lost to follow-up and were excluded.

Of the remaining 1054 participants, 640 were not taking ACEIs and 414 were taking ACEIs during the study, including 274 taking centrally active ACEIs and 185 taking ACEIs that did not cross the blood-brain barrier. Mean age in the evaluated cohort was 74.8 ± 4.9 years; 64% were women and 76% were white.

There were 2 primary outcome measures: incident all-cause dementia, based on a diagnosis determined by a committee that reviewed results of magnetic resonance imaging and other tests and clinical findings; and change in cognitive function on the Modified Mini Mental State Examination (3MSE; scale of 0–100), with higher scores reflecting better cognition.

The investigators used Cox proportional hazards models to estimate the risk of incident dementia associated with cumulative exposure to ACEIs as a class and to centrally active vs noncentrally active ACEIs as time-dependent predictors, incorporating a 1-year delay between exposure and outcome. Analyses of covariance with repeated measures were used to determine the change in 3MSE scores, adjusted in a stepwise fashion for demographics (age, race, sex, income), health behaviors (smoking, alcohol, exercise), comorbidities (creatinine, low-density lipoprotein cholesterol, C-reactive protein, diabetes, coronary artery disease), baseline 3MSE, apolipoprotein E genotype, incident stroke, annual systolic blood pressure, and use of other antihypertensive drugs.

During follow-up, there were 159 cases of incident dementia. When use of all ACEIs was compared with use of other antihypertensive drugs, there was no increasedrisk of dementia (hazard ratio [HR], 1.02, 95% confidence interval [CI], 0.88–1.18) or difference in 3MSE scores over time (0.14 points/year, P = .16). Adjustment for potential confounders did not affect these results.

However, the use of centrally active ACEIs was associated with a decline in 3MSE scores 50% less than that associated with the use of other antihypertensive agents. After adjustment for covariates, annual changes in 3MSE scores were –0.32 and –0.64, respectively (P = .04).

"These results are promising, but we need to confirm them in a randomized controlled trial [in which] some people are assigned to ACE inhibitors that get into the brain and some are assigned to ones that don't," Dr. Sink said.

Study limitations include inability to completely rule out confounding by indication; inability to differentiate early from late exposure; and failure to account for dose of medications, only for the duration of use.

"[This report] explores a new and novel hypothesis with a well-conducted longitudinal study," David B. Reuben, MD, Chief of Geriatrics at University of California at Los Angeles (UCLA), told Medscape. "The limitations are that it is a single study and uses an observational design."

Dr. Reuben, who is also Director of the Multicampus Program in Geriatric Medicine and Gerontology and Archstone Professor of Medicine at the David Geffen School of Medicine at UCLA, was not involved in this study, but was asked by Medscape to provide independent commentary.

"Within the class of ACEIs, individual drugs that are centrally active may protect against the development of dementia," Dr. Reuben concluded. "If these findings are confirmed, then it might help to guide the choice of antihypertensive agents in this commonly used class of drugs."

The National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) funded collection of the CHS data. Dr. Sink is supported by the Hartford Geriatrics Health Outcomes Research Scholars program, the Pepper Older Adults Independence Center (NIH grant), and the Wake Forest University Kulynych Center on Cognition and Memory Research. Drs. Sink and Reuben report no relevant financial relationships.

AGS 2007 Annual Scientific Meeting: Abstract P36. Presented May 5, 2007.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.