ARBs May Reduce Incidence of Alzheimer's Over ACE Inhibitors, but Combination May Be Best

Susan Jeffrey

January 28, 2010

January 28, 2010 — A new study shows a significant reduction in the incidence of Alzheimer's disease (AD) and dementia among subjects taking angiotensin receptor blockers (ARBs) compared with those taking angiotensin-converting enzyme (ACE) inhibitors or other cardiovascular drugs.

Further, there appeared to be a reduction in rates of disease progression, indicated by the time to admission to a nursing home or death, among those taking ARBs, the study authors note.

"We also saw that the people who did the best appeared to be those who were taking ARBs together with ACE inhibitors, " senior author Benjamin Wolozin, MD, PhD, from Boston University School of Medicine in Massachusetts and the Center for Health Quality Outcomes and Economic Research, Veterans Affairs Medical Center, Bedford, Massachusetts, told Medscape Neurology.

"There, the data actually gets very striking; we saw a 55% lower incidence of Alzheimer's or dementia, and a 70% decrease in nursing home admissions," Dr. Wolozin added.

Their report was published online January 12 in the BMJ.

Protective Effect

ARBs selectively inhibit the AT1 receptor, and although slightly less effective at lowering blood pressure than ACE inhibitors, they have been shown in an increasing number of studies to be related to preservation of cognitive function through a mechanism independent of their antihypertensive action, the study authors write.

In this study, Dr. Wolozin and colleagues used data from the US Veterans Affairs administrative database to look at time to incident AD or dementia during a 4-year period in 3 prospective cohorts. Participants were predominantly male and 65 years and older, with a diagnosis of cardiovascular disease. One group included subjects taking an ARB, a second included those taking the ACE inhibitor lisinopril, and a third comparator group were taking other cardiovascular drugs, excluding ARBs, ACE inhibitors, and statins.

Among those with a previous diagnosis of AD or dementia, disease progression was defined for these purposes as the time to admission to a nursing home or death.

After adjustment for age, diabetes, stroke and cardiovascular disease, incident AD, and particularly incident dementia were reduced with the ARB vs both the ACE inhibitor and the cardiovascular comparator group.

Table 1. Risk for Incident Alzheimer's Disease and Dementia With ARB Treatment vs Lisinopril and a Cardiovascular Comparator

Outcome Hazard Ratio (95% CI) P Value
Incident Alzheimer's disease    
ARB vs lisinopril 0.81 (0.68 – 0.96) .016
ARB vs cardiovascular comparator    
Incident dementia 0.84 (0.71 – 1.00) .045
ARB vs lisinopril 0.81 (0.73 – 0.90) <.001
ARB vs cardiovascular comparator 0.76 (0.69 – 0.84) <.001

ARB = angiotensin receptor blocker; CI = confidence interval

Among those who already had AD, treatment with an ARB was associated with a significantly lower risk of admission to a nursing home or death during the follow-up period.

"Angiotensin receptor blockers exhibited a dose response as well as additive effects in combination with angiotensin-converting enzyme inhibitors," the study authors note. Compared with the ACE inhibitor alone, the combination was associated with a significantly reduced risk of incident AD and dementia and admission to a nursing home.

Table 2. Risk for Dementia and Nursing Home Admission With Combined ARB and ACE Inhibitors vs ACE Inhibitor Alone

Outcome Hazard Ratio (95% CI) P Value
Incident Alzheimer's disease 0.45 (0.41 – 0.50) <.001
Incident dementia 0.54 (0.51 – 0.57) <.001
Nursing home admission 0.33 (0.22 – 0.49) <.001

ACE = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CI = confidence interval

"I actually find that nursing home finding very striking because you can imagine the big impact if you could avoid going to a nursing home," Dr. Wolozin told Medscape Neurology. Still, other factors play a role in this decision, including caregivers' situations and financial resources, he added.

The investigators point out that stroke was consistently ranked the most important covariate in this data set, suggesting the importance of vascular factors in the progression of cognitive loss. ARBs also have been shown to be effective in preventing vascular damage induced by amyloid-β that accumulates in AD, they note.

"Because vascular dysfunction and stroke are associated with cognitive decline, our data raise the possibility that combined use of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors might confer superior protection against cognitive decline (compared with other cardiovascular drugs) by reducing neuronal damage associated with stroke and vascular dysfunction," the study authors speculate.

Complex Mechanisms

In an editorial appearing with the paper, Colleen J. Maxwell and David B. Hogan, both from the University of Calgary, Alberta, point out that the reason that ARBs may be superior to ACE inhibitors is that the AT1 and AT2 receptors have "complex and nonidentical mechanisms of action."

"Stimulation of type 1 receptors causes vasoconstriction, whereas stimulation of type 2 receptors reportedly leads to vasodilatation, neuronal differentiation, apoptosis, and axonal regeneration," they write. ARBs selectively inhibit the type 1 receptors, which might translate to improved cerebral blood flow and enhanced neuroprotective effect.

Still, they point out that the randomized clinical trials SCOPE (Study on Cognition and Prognosis in the Elderly)and PRoFESS (PReventiOn regimen For Effectively avoiding Second Strokes) showed no significant effect on either the rate of cognitive decline or incident dementia with an ARB.

Limitations of the study include the nonrandomized allocation of treatment, which they call a "serious problem" because racial disparities have been reported in the use of antihypertensives, such as ARBs, among American veterans and the ethnic origin of most subjects was not reported.

"The public health implications of finding an effective way of preventing dementia are immense, but further work is needed to verify the usefulness of antihypertensives in general and angiotensin receptor blockers in particular," they conclude.

The study was supported by a grant to Dr. Wolozin from the Retirement Research Foundation and a donation from the Casten Foundation. Dr. Wolozin reports having received these grants as disclosure of competing interests in the paper. The editorialists have disclosed no relevant financial relationships.

BMJ. Published online January 12, 2010 .

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