ACE Inhibitors May Slow Cognitive Decline

Pauline Anderson

July 29, 2013

Centrally acting angiotensin-converting enzyme inhibitors (CACE-Is) reduce the rate of cognitive decline in patients with dementia, regardless of blood pressure levels at the time of their hypertension diagnosis, a new study has found.

The study also shows that the rate of cognitive change was improved in the first 6 months after dementia patients started taking these drugs.

"There's a growing body of literature now showing that these drugs slow down the deterioration that people with Alzheimer's disease experience, probably by between 20% and 30% a year compared to another antihypertensive drug or no centrally acting ACE inhibitor," said study author D. William Molloy, professor, Center for Gerontology and Rehabilitation, University College Cork, Cork City, Ireland.

The results prompt the question of whether these CACE agents would actually delay or prevent the onset of Alzheimer's disease (AD) in people with normal blood pressure who are at risk for dementia, said Dr. Molloy.

The study was published online July 22 in BMJ Open.

Significant Change

Researchers used the Geriatric Assessment Tool (GAT) database, which contains over 8000 physician assessments of 1749 people aged 41 to 104 years. The data, collected from 1999 to 2010, includes age, sex, education, medical diagnoses, blood pressure, laboratory findings, medications, and other measures from patients at 2 university hospitals in Hamilton, Ontario, Canada. It also includes the scores of 2 cognitive screening tests — the Standardized Mini-Mental State Examination (SMMSE) and the Quick Mild Cognitive Impairment (Qmci) screen. The Qmci has 6 subtests covering 5 cognitive domains: orientation, working memory, semantic memory, visual spatial, and 2 tests of episodic memory.

The analysis included only patients with AD, vascular or mixed dementias (Alzheimer's/vascular). These patients were grouped into those not taking a CACE inhibitor (the NoCACE-I group; n = 276) and those prescribed a CACE inhibitor (the CACE-I group; n = 85). (CACE inhibitors include perindopril, ramipril, trandolapril, captopril, fosinopril, lisinopril, and prinivil.) The researchers also looked at a group of 30 patients who began receiving a CACE inhibitor within the previous 6 months (NewCACE-I group).

Dr. D. William Molloy

The rate of cognitive decline was defined as the baseline cognitive score minus the endpoint score times 6 divided by duration in months.

The study found that the median change in SMMSE scores between the baseline and endpoint was 0.69 point per 6 month. The median SMMSE score differences for the CACE-I, NoCACE-I, and New CACE-I groups were 0.8, 1.0, and -1.2, respectively, per 6 months. For the Qmci, the median change was 2 points per 6 months, with median Qmci score differences for the CACE-I and NoCACE-I groups of 1.8 and 2.1, respectively, per 6 months.

There was a borderline significant difference in the median 6-month rate of decline in Qmci scores between CACE-I (1.8 points) and NoCACE-I (2.1 points) (P = .049). There were similar but nonsignificant changes in SMMSE (P = .77).

Newly treated patients also showed improvements. The median decline in scores for the NewACE-I group on the SMMSE was -1.2 points during the first 6 months of taking the drug.

Unlike some studies that show significant change but aren't clinically significant, this study uncovered a more definitive effect from use of CACE-I drugs, said Dr. Molloy. "This was clearly clinically significant, I think; it's not just Mickey Mouse change; it's significant change."

Among the different CACE-I agents, perindopril appeared to outperform the others, according to Dr. Molloy. "From the data we looked at, my impression was that perindopril was better than ramipril. It has a longer half-life so it has a smoother action over 24 hours, and it might have better tissue penetration."

It didn't seem to matter how long patients had been taking a CACE-I. Researchers didn't have enough data on dosage to determine whether this affected the rate of cognitive decline, said Dr. Molloy.

What's clear from this study is that CACE-I drugs, which are lipid soluble, do not work by lowering blood pressure, said Dr. Molloy. "We show here that in the ACE inhibitor class, it's the ones that cross the blood-brain barrier that are having the effect, suggesting that it's not a blood pressure–lowering effect, that there's something about this penetration of the central nervous system."

Anti-inflammatory Effect

But it's not clear how CACE drugs actually slow down cognitive decline in patients with AD. Dr. Molloy believes, though, that AD is probably the result of chronic inflammation in the brain and that CACEs have an effect on that inflammation.

"By crossing over, they may penetrate the tissues and they may be having some kind of anti-inflammatory effect or somehow switch off the inflammation," he said.

Quite Exciting

Dr. Molloy found the study results "quite exciting," especially the finding that the drugs seem to have an effect even after patients have been taking them for many years. The study, he said, offers some new hope for patients with AD. "We don't have a handle on Alzheimer's disease at all; we don't have anything to prevent it, and we don't really have much to slow it down."

Tempering that excitement, however, is the concern that in some people, ACE inhibitors might interfere with degradation of amyloid-β, thereby contributing to increase amyloid burden. It could be, said Dr. Molloy, that AD isn't a homogenous disease, that in some people it's more an issue of accumulating amyloid-β than a problem with inflammation.

A limitation of the study was that many patients in the database did not have both SMMSE and Qmci results at baseline and at the end of the study, limiting the numbers that could be included in the analysis. As well, different effects may have become apparent had the analysis covered a longer period.

The study results are only observational, and Dr. Molloy wants to "toss the coin" and test the findings in a clinical trial. "I would love to do a proper randomized trial of a centrally acting ACE inhibitor versus a non–centrally acting ACE inhibitor and treat patients for a couple of years and see what happens."

In addition to ACE inhibitors, other antihypertensive drugs have been associated with a lower risk of developing dementia, including calcium channel blockers, diuretics, and angiotensin-receptor blockers.

According to background information in the paper, about 80 million people worldwide will be affected by dementia by the year 2040.

Support for Previous Findings

Medscape Medical News sought the opinion of Kaycee M. Sink, MD, associate professor of medicine, director of the Kulynych Memory Assessment Clinic, Wake Forest School of Medicine, Salem, North Carolina, who has done research in this area.

"The results of this study add support to previous findings, including our own, that centrally active ACE inhibitors may be beneficial to cognition," said Dr. Sink.

However, the impact of the study is lessened by limitations of the study, which include the small sample size, possible confounding by indication (not everyone had an indication for an ACE inhibitor or even a blood pressure medication), and a very small effect size (probably not clinically significant).

"I don't think clinicians should use this study to support starting patients with dementia on a centrally active ACE inhibitor for treatment of dementia," said Dr. Sink. "However, if a patient has an indication for an ACE inhibitor (for example, hypertension, congestive heart failure, chronic kidney disease), then choosing a centrally active ACE inhibitor rather than a non–centrally active one probably makes sense."

The Centre for Gerontology and Rehabilitation is funded by Atlantic Philanthropies, the Health Services Executive Ireland, the Irish Hospice Foundation, and the Canadian Institutes of health Research. The authors have disclosed no relevant financial relationships.

BMJ Open. Published online July 22, 2013. Full text

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