ACE inhibitors may slow cognitive decline

Cork, Ireland and Hamilton, ON - Centrally acting ACE inhibitors 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 [1]. 


The study also shows that the rate of cognitive change was improved in the first six 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 with another antihypertensive drug or no centrally acting ACE inhibitor," said study author Dr D William Molloy (University College Cork, Ireland). The results raise the question of whether these agents would actually delay or prevent the onset of Alzheimer"s disease in people with normal blood pressure who are at risk of dementia, he said.

The study was published online July 22, 2013 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, include age, gender, education, medical diagnoses, blood pressure, laboratory findings, and medications from patients at two university hospitals in Hamilton, ON. It also includes the scores of two cognitive screening tests covering five cognitive domains: orientation, working memory, semantic memory, visual spatial, and two tests of episodic memory.

The analysis included only subjects with Alzheimer’s disease or vascular or mixed dementias (Alzheimer’s/vascular). These subjects were grouped into those not taking a centrally acting ACE inhibitor (the NoCACE-I group; n=276) and those prescribed a centrally acting ACE inhibitor (the CACE-I group; n=85). The researchers also looked at a group of 30 subjects who were started on a centrally acting ACE inhibitor within the previous six months (the NewCACE-I group).

The study found participants taking centrally acting ACE inhibitors had slightly slower rates of cognitive decline than those not taking the drugs.

Newly treated patients also showed improvements in cognitive scores. The median decline in scores for the NewACE-I group on the Standardized Mini-Mental State Examination (SMMSE) was -1.2 points during the first six months of taking the drug.

Unlike some studies that show significant change but aren’t clinically significant, this study uncovered a more definitive impact from use of centrally acting ACE inhibitors, said Molloy. "This was clearly clinically significant; I think; it’s not just Mickey Mouse change; it’s significant change."

Among the different agents, perindopril appeared to outperform the others, according to 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 subjects had been taking an ACE inhibitor. Researchers didn’t have enough data on dosage to determine whether this had an impact on the rate of cognitive decline, said Molloy.

What’s clear from this study is that centrally acting ACE inhibitors, which are lipid soluble, are not working by lowering blood pressure, said 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 

While it’s not clear how these drugs actually slow down cognitive decline in Alzheimer’s patients, Molloy believes that the disease is probably the result of chronic inflammation in the brain and that ACE inhibitors 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.

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 a number of years. The study, he said, offers some new hope for Alzheimer’s disease patients. "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 beta, thereby contributing to increase amyloid burden. It could be, said Molloy, that Alzheimer’s disease isn’t a homogenous disease, that in some people it’s more an issue of accumulating amyloid beta than a problem with inflammation.

A limitation of the study was that many patients in the database did not have both SMMSE and other test 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.

Also, the study results are only observational. "I would love to do a proper randomized trial of a centrally acting ACE inhibitor vs a non-centrally acting ACE inhibitor and treat patients for a couple of years and see what happens," Molloy said.

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.

Support for previous findings

Asked to comment on the study, Dr Kaycee M Sink (Wake Forest School of Medicine, Salem, NC), who has done research in this area, noted that the new study results add support to previous findings, "including our own, that centrally active ACE inhibitors may be beneficial to cognition."

However, the impact of the study is lessened by limitations of the study that 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 (likely 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 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."

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