ACE Inhibitors and Alzheimer's Disease

Oct. 14, 2004 — Brain-penetrating angiotensin-converting enzyme (ACE) inhibitors may reduce progression of dementia in Alzheimer's disease (AD), according to the results of a preliminary randomized trial published in the Oct. 12 issue of Neurology.

"There is evidence that certain components of the reninangiotensin system (RAS) may have a crucial role in learning and memory processes," write T. Ohrui, MD, and colleagues from Tohoku University School of Medicine in Japan. "We have shown that brain-penetrating ACE inhibitors can reduce the incidence of AD in elderly hypertensive patients."

In this prospective, parallel group trial with one-year exposure to study medications, participants were recruited from three long-term care facilities in Sendai, Japan. Eligibility criteria were a diagnosis of mild to moderate AD based on National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, age 65 years or older, Mini-Mental State Examination (MMSE) scores from 13 to 23, and blood pressure higher than 140 mm Hg systolic or 90 mm Hg diastolic.

Exclusion criteria were evidence of stroke, insulin-dependent diabetes mellitus or other endocrine disorder, asthma or obstructive pulmonary disease, clinical or laboratory evidence of a cause other than AD for dementia, possible or probable vascular dementia and other neurodegenerative dementias based on brain magnetic resonance imaging, and poorly controlled hypertension, congestive heart failure, renal failure, psychiatric disorders such as schizophrenia, or drug or alcohol abuse.

Of 183 patients screened, 162 were randomized in December 2002 to receive a brain-penetrating ACE inhibitor (perindopril 2 mg/day or captopril 37.5 mg/day; group A), a non–brain-penetrating ACE inhibitor (enalapril 5 mg/day or imidapril 5 mg/day; group B), or a calcium-channel blocker (nifedipine 20 mg/day or nilvadipine 4 mg/day; group C) .

Age, comorbid diseases, baseline MMSE, and use of cholinesterase inhibitor (donepezil), statins, or low-dose aspirin were similar among the three groups.

During 12-month follow-up, all participants had a stable and comparable blood pressure under antihypertensive treatment, except for one patient in group C who dropped out of the study because of hypotension. Mean decline in MMSE scores in group A (0.6 ± 0.1, n = 51) was lower than in group B (4.6 ± 0.3, n = 53; P = .0023) or in group C (4.9 ± 0.3, n = 57; P < .001).

The primary limitation of this study was that the declining rate of MMSE scores in group B or group C was more pronounced than in an earlier study.

"These results suggest that brain-penetrating ACE inhibitors might have a clinical benefit even in patients with limited activities of daily living, who might have shown a rapid decline in MMSE scores if not assigned to these drugs," the authors write. "Brain-penetrating ACE inhibitors might have benefits not only for the prevention but also for the treatment of mild to moderate AD."

In an accompanying commentary, David S. Knopman, MD, called these findings "provocative and exciting" but noted several methodologic weaknesses mandating replication in carefully controlled, randomized, blinded studies.

"It is not clear whether perindopril, captopril, or both drove the effect. The amount of decline in the other two groups was much larger than expected," Dr. Knopman writes. "The lack of adverse events is surprising and the extremely high retention rate of patients in both arms of the study is unusual. Moreover, despite the randomization, the medications were not administered in a blinded fashion."

Neurology. 2004;63:1145, 1324-1325

Reviewed by Gary D. Vogin, MD