Centrally Active ACE Inhibitors May Help Prevent Dementia

Janis Kelly

July 23, 2009

July 23, 2009 ( updated July 28, 2009 ) — New observational data from the Cardiovascular Health Study show that centrally active angiotensin-converting enzyme (ACE) inhibitors reduce cognitive decline by 65% per year of exposure, an effect that is likely due to their ability to cross the blood-brain barrier.

"If confirmed in a randomized clinical trial, our findings would add another potential therapeutic option" for prevention of cognitive decline and related diseases, lead author Kaycee M. Sink, MD, from Wake Forest University School of Medicine, in Winston-Salem, North Carolina, told Medscape Neurology.

The study is published in the July 13 issue of Archives of Internal Medicine.

Class of ACE Inhibitor Important

Dr. Sink and colleagues used data from the Cardiovascular Health Study to determine whether cumulative exposure to ACE inhibitors was associated with a lower risk for incident dementia, cognitive decline, or incident disability in instrumental activities of daily living (IADLs), compared with treatment with other antihypertensive agents in 1054 patients with treated hypertension and no congestive heart failure.

The study included 414 subjects who had taken ACE inhibitors and 640 who had taken other antihypertensive medications. The researchers found no association between exposure to all ACE inhibitors and risk for dementia, difference in cognitive-function scores, or odds of disability in IADLs.

However, analysis according to type of ACE inhibitor showed a different effect. The results showed centrally active ACE inhibitors were associated with 65% less decline in cognitive-function scores per year of exposure.

The data also reveal that non–centrally active ACE inhibitors were associated with a greater risk for incident dementia and greater odds of disability in IADLs compared with other antihypertensive medications.

Centrally active ACE inhibitors included captopril (Capoten, Bristol-Myers Squibb), fosinopril (Monopril, Bristol-Myers Squibb), lisinopril, perindopril, ramipril (Altace, King Pharmaceuticals), and trandolapril (Mavik, Abbott Laboratories). Non–centrally active ACE inhibitors included benazepril (Lotensin, Novartis Pharmaceuticals), enalapril (Vasotec, Merck), moexipril (Univasc, Schwarz Pharma), and quinapril (Accupril, Pfizer).

The study did not include enough people taking angiotensin receptor blockers (ARBs) to extend the analysis to those drugs, said Dr. Sink.

Reduced Incidence Likely Not Due to Antihypertensive Effect

"Our most important findings in this observational study were that centrally acting ACE inhibitors were associated with a 65% reduction in cognitive decline per year of taking the centrally active ACE inhibitors," said Dr. Sink.

"In addition, compared with participants with high blood pressure who took other types of blood-pressure–lowering medications, non–centrally active ACE inhibitors did not have this effect and might be associated with a greater risk for incremental dementia, and  that cumulative (or chronic) exposure to ACE inhibitors may be needed to achieve the protective effect," Dr. Sink said.

The researchers suspect that this difference is due primarily not to the antihypertensive effects of centrally acting ACE inhibitors but to their effect on the brain's intrinsic renin-angiotensin system, which is involved in memory and cognition.

Stimulation of the renin-angiotensin system also mediates activation of inflammatory cytokines that have been implicated in degenerative dementias, explained Dr. Sink.

The researchers also suspect that the slight increase in dementia risk associated with the non–centrally acting ACE inhibitors in this comparison was probably a sign that they are "simply less helpful in the prevention of dementia and IADL disability than other antihypertension drug classes combined."

Due to the huge public-health implications of finding an intervention that could more than halve dementia risk in the elderly population, confirmation of these observational findings in a randomized clinical trial is needed.

"Randomizing older adults with hypertension to a centrally active ACE inhibitor vs a non–centrally active ACE inhibitor would test the hypothesis that centrally active ACE inhibitors have protective benefits on cognition beyond the effects of blood-pressure control," said Dr. Sink.

Should Patients Switch Medications?

Whether clinicians should switch their hypertensive patients to a centrally acting ACE inhibitor must be decided on a case-by-case basis, said Dr. Sink.

"Because there are often multiple reasons for a particular choice of antihypertensive drug in any particular patient, the decision about switching blood-pressure medications should be discussed between patient and provider.

"However, if the patient does not have a contraindication for an ACE inhibitor, then switching to a centrally active ACE inhibitor is a reasonable choice. In addition, for those already on ACE inhibitors, our study results would support the use of a centrally active ACE inhibitor over a non–centrally active one," Dr. Sink said.

Asked by Medscape Neurology to comment on the findings, Ihab Hajjar, MD, from the Institute for Aging Research and assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts, said that this study adds to the support for clinical trials.

"This is the right time to study ACE inhibition on cognitive function. However, it is important to select the appropriate drug [agents that cross the blood-brain barrier] and the appropriate population [hypertensives and other high-risk groups]," Dr. Hajjar said in an interview.

However, he emphasized that lowering blood pressure is the most important goal for managing high-risk elderly patients and that the choice of drug is secondary.

"Drugs that inhibit the renin angiotensin system seem to have a preferential effect on cognition compared with other antihypertensives. As a third issue, antihypertensives that cross the blood-brain barrier may also have an even superior effect to  other non–blood-brain-barrier-penetrating drugs. This is true not only for those without cognitive impairment but also for those with dementia and Alzheimer's disease," Dr. Hajjar said.

Study investigator David C. Goff Jr., MD, PhD, from Wake Forest University, has a research grant from Merck. The study was supported in part by the National Heart, Lung, and Blood Institute; the National Institute of Neurological Disorders and Stroke; and the National Institute on Aging.

Arch Intern Med. 2009;169:1195-1202. Abstract