ACE inhibitors that penetrate the blood-brain barrier may slow Alzheimer's progress

Researchers have found that angiotensin-converting enzyme (ACE) inhibitors that penetrate the blood-brain barrier (BBB) appear to reduce the incidence of Alzheimer's disease (AD) in elderly patients with hypertension. In a randomized, prospective, parallel group trial (N=162), patients given 1 of 2 brain-penetrating inhibitors (perindopril 2 mg/d or captopril 37.5 mg/d) exhibited smaller declines in Mini-Mental State Examination (MMSE) scores compared with patients in 2 other treatment groups.

Evidence exists that certain components of the renin-angiotensin system (RAS) may have a role in learning and memory processes. The ACE gene is over-expressed in the hippocampus, frontal cortex, and caudate nucleus of patients with AD. In animal models, brain-distributing ACE inhibitors were shown to rescue neuronal damage and improve behavior.

The current study tested the hypothesis that treatment with ACE inhibitors that penetrate the BBB would slow the rate of cognitive decline in patients with mild-to-moderate AD and hypertension. Eligible patients were aged 65 or older; had MMSE scores between 13 and 23; showed no evidence of stroke, insulin-dependent diabetes, asthma, or obstructive pulmonary disease; and had a systolic blood pressure >140 mmHg and diastolic blood pressure >90 mmHg. Participants had no other clinical cause for dementia other than AD.

The primary analysis was a comparison of the change in MMSE scores between Group A and Group B or Group C. Mean decline in MMSE scores in Group A (0.6±0.1) was lower compared to Group B (4.6±0.3; P=.0023) and Group C (4.9±0.3; P<.001). The researchers suggested that the favorable results with the BBB-penetrating ACE inhibitors may be due to effects of the drug on RAS in the brain, since no differences were seen among the 3 groups with regard to blood-pressure levels. Another possible mechanism is an increased level of brain substance P (SP) by ACE inhibitors. Increased SP can augment the activity of neprilysin, which may improve the outlook for the progression of AD.

A limitation of the study was that the declining rate of MMSE scores in Groups B and C was more pronounced in this study compared with a previous study. Researchers reevaluated the scores of participants in Groups B and C who showed a rapid decline (more than 6 points per year), and found that they had limited activities of daily living (ADL). However, no significant differences were found in the proportion of frail AD patients with limited ADL. Study results suggest that ACE inhibitors may have clinical benefit even in patients with limited ADL.

In an accompanying commentary, David S. Knopman, MD, observed that the "study's findings are provocative and exciting, but readers must be skeptical." He explained: "It is not clear whether perindopril, captopril, or both drove the effect." Dr Knopman also expressed concern about the lack of adverse events, the high retention rate of patients in both study arms, and the fact that the medications were not administered blindly.

SOURCES Ohrui T, Tomita N, Sato-Nakagawa T, et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology. 2004;63: 1324-1325.

Knopman DS. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression: A handful of ACEs? Neurology. 2004;63:1145.