Nancy A. Melville

October 31, 2016

BALTIMORE — Use of antihypertensive medications targeting the renin-angiotensin system (RAS) during life is associated with a reduction in neurofibrillary tangles on postmortem examination compared with use of non-RAS antihypertensives, suggesting a possible mechanism for the slowing of Alzheimer's disease progression that has previously been shown with the drugs, according to new research.

"Individuals taking RAS-acting antihypertensives for at least three years were less likely to convert from mild cognitive impairment [MCI] to Alzheimer's disease and showed fewer neurofibrillary tangles compared to individuals taking non-RAS acting antihypertensives," the authors reported.

In a previous study of 784 patients with MCI at baseline, published in the Journal of the American Geriatric Society, the researchers, from Emory University School of Medicine, Atlanta, Georgia, found that those taking RAS-acting medications, specifically centrally acting angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), were less likely to convert to Alzheimer's disease (P = .04) and had slower declines in dementia measures (P =.01) compared with nonusers over 3 years, with a stronger effect in African Americans.

For the new study, presented here at the American Neurological Association (ANA) 2016 Annual Meeting, the researchers further investigated the mechanisms behind the effect, looking at data, including postmortem neuropathologic information, from 83 patients in Rush University Alzheimer's Disease Center (Rush ADRC) who had MCI at baseline.

Patients were taking an antihypertensive at baseline and during at least two consecutive follow-up visits, with 38 of the patients taking RAS medication and 45 taking non-RAS medication.

The patients had no significant differences in demographic characteristics; 32% were male, and 9.2% were black. They had a mean baseline Mini-Mental State Examination score of 26 and a mean age of 82 years; 28% were APOE4-positive.

Of the patients, 14 converted to Alzheimer's disease during the study.

Consistent with the previous studies, patients taking RAS medication were significantly less likely to progress to Alzheimer's disease (3 patients, 7.9%) than non-RAS users (11 patients, 24.4%; P = .02).

Notably, those taking the RAS-acting medications had significantly fewer neurofibrillary tangles than did non-RAS users overall (P = .03), and the differences were seen in all prespecified brain regions of interest, including the entorhinal cortex (P = .04) and the hippocampal CA1 region (P =.01).

There were no significant differences in the groups in other neuropathologic measures, including brain weight; amyloid burden; National Institute on Aging–Reagan, CERAD (Consortium to Establish a Registry for Alzheimer’s Disease), or Braak scores; diffuse plaques; or arteriolosclerosis.

While blood pressure or cholesterol levels did not differ between groups, more patients in the RAS user group had diabetes (P = .01). This finding was notable, first author Whitney Wharton, PhD, from the Department of Neurology at Emory University School of Medicine, told Medscape Medical News.

"The RAS users were less likely to progress to Alzheimer's disease and had less tangles, even though they were more likely to have diabetes and were therefore a less healthy group," she said.

"One would think that the sicker group would have more tangles and overall brain neuropathology, but this is not what we saw. Therefore, it is possible that if we looked at an equally healthy sample at baseline, our results would be even stronger."

An important caveat of the findings is that RAS-acting medications are not recommended as a first line of defense for African Americans, who happen to have a higher risk for Alzheimer's disease, as well as high blood pressure, which is, in itself, an independent risk factor for Alzheimer's, Dr Wharton noted.

"If we are going to help prevent Alzheimer's disease in the most people possible, as quickly as possible, we need to focus our research efforts on populations who need the most help and who have the most potential to gain from an intervention," she said.

In continuing research, Dr Wharton and her colleagues are evaluating the role of RAS-acting antihypertensive medications in African Americans with a family history of Alzheimer's disease.

If replicated, the current study's findings could have important clinical implications, said Steven M. Greenberg, MD, PhD, the John J. Conway Endowed Chair of the Department of Neurology at Massachusetts General Hospital and professor of neurology at Harvard Medical School, in Boston, Massachusetts.

"The results suggest a mechanism for the authors' previous finding that RAS-active drugs slow dementia progression, raising the possibility that they somehow slow tangle formation," he told Medscape Medical News.

"If this mechanism could be confirmed, it would add substantially to potential treatment approaches for preventing this important pathologic change."

He noted that, considering what's known about the RAS pathway, the link with neurofibrillary tangles and Alzheimer's is feasible.

"The RAS pathway appears to be involved in a lot of biological processes, so it's not entirely surprising that these drugs might have effects outside of modulating blood pressure.  The finding will still require confirmation from other data sets."

Furthermore, "the mechanisms that actually regulate tau hyperphosphorylation and deposition and tangle formation have not been entirely worked out, but there is certainly potential for overlap with these RAS-dependent pathways," he added.

Dr Greenberg noted that important limitations of the study include some potential confounders.

"Patients were not randomly assigned to receive RAS medications, which allows for potential confounding by indication, ie, that the people who received these medications were systematically different from the people who didn't," he explained.

"There is also the possibility of a chance association with tangles that will not hold up in a replication study.  Some type of confirmation will be key."

The research was funded by grants from the National Institutes of Health/National Institute on Aging. The authors have disclosed no relevant financial relationships. Dr Greenberg is a safety monitor on Alzheimer's disease trials, including the DIAN-TU and trials conducted by Roche and Biogen.

American Neurological Association (ANA) 2016 Annual Meeting. Abstracts M126. Presented October 17, 2016.

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