Seattle, WA - Compared with other antihypertensive agents, centrally active ACE inhibitors are associated with slower rates of cognitive decline over six years in elderly people free of dementia at baseline, according to findings from the Cardiovascular Health Study (CHS) presented here at the annual meeting of the American Geriatrics Society [1].

"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 Dr Kaycee M Sink (Wake Forest University School of Medicine, Winston-Salem, NC) said.

Centrally active ACE inhibitors, such as captropril (Capoten, Bristol-Myers Squibb), fosinopril (Monopril, Bristol-Myers Squibb), lisinopril (Prinivil, Merck; Zestril, AstraZeneca), perindopril (Aceon, Solvay Pharmaceuticals), ramipril (Altace, King Pharmaceuticals), and trandolapril (Mavik, Abbott Laboratories), cross the blood-brain barrier. Previous animal studies suggest that centrally active ACE inhibitors 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," 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 from Forsyth County, NC; Sacramento County, CA; Pittsburgh, PA; and Washington County, MD. 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 six years; 20 participants were lost to follow-up and were excluded.

Of the remaining 1054 participants, 640 were not taking ACE inhibitors and 414 were taking ACE inhibitors during the study, including 274 taking centrally active ACE inhibitors and 185 taking ACE inhibitors 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 two 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 (MMSE; 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 ACE inhibitors as a class and to centrally active vs noncentrally active ACE inhibitors as time-dependent predictors, incorporating a one-year delay between exposure and outcome. Analyses of covariance with repeated measures were used to determine the change in MMSE scores, adjusted in a stepwise fashion for demographics (age, race, sex, income), health behaviors (smoking, alcohol, exercise), comorbidities (creatinine, LDL cholesterol, C-reactive protein, diabetes, coronary artery disease), baseline MMSE, 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 ACE inhibitors was compared with use of other antihypertensive drugs, there was no increased risk of dementia (HR 1.02; 95% CI 0.88-1.18) or difference in MMSE scores over time (0.14 points/year, p=0.16). Adjustment for potential confounders did not affect these results.

However, the use of centrally active ACE inhibitors was associated with a decline in MMSE scores that was 50% less than that associated with the use of other antihypertensive agents. After adjustment for covariates, annual changes in MMSE scores were -0.32 and -0.64, respectively (p=0.04).

"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," 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," Dr David B Reuben (University of California, Los Angeles), who was asked for commentary, said. "The limitations are that it is a single study and uses an observational design."

"Within the class of ACE inhibitors, individual drugs that are centrally active may protect against the development of dementia," 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."