Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression

Methods.

We performed a randomized, prospective, parallel group trial with 1-year exposure to study medications. Participants were recruited from three long-term care facilities in Sendai, Japan. Patients eligible for this study had a diagnosis of mild to moderate AD,4,5⇓ were aged 65 years and older, had Mini-Mental State Examination (MMSE) scores within the range of 13 to 23, showed no evidence of stroke; insulin-dependent diabetes mellitus, or other endocrine disorders, or asthma or obstructive pulmonary disease, and had a blood pressure of higher than 140 mm Hg systolic or 90 mm Hg diastolic. The diagnosis of probable AD was made according to National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria with no clinical or laboratory evidence of a cause other than AD for dementia.5 Brain MRI was obtained in all participants within 3 months prior to the study enrollment to exclude patients with possible or probable vascular dementia and other neurodegenerative dementias. Patients were excluded if they had poorly controlled hypertension, congestive heart failure, renal failure, psychiatric disorders such as schizophrenia, or drug or alcohol abuse.

We screened 183 patients and 162 were entered into the study and randomly assigned (by a randomization table) to a brain-penetrating ACE inhibitor (perindopril 2 mg/day or captopril 37.5 mg/day) group (n = 51 [11 men], mean age 76 ± 2 [standard error; SE] years) (Group A), a non brain-penetrating ACE inhibitor (enalapril 5 mg/day or imidapril 5 mg/day) group (n = 53 [12 men], mean age 77 ± 3 years) (Group B), or a calcium-channel blocker (nifedipine 20 mg/day or nilvadipine 4 mg/day) group3 (n = 58 [14 men], mean age 75 ± 2 years) (Group C) in December 2002 (see figure E-1 on the Neurology Web site at www.neurology.org). Reasons for screening failure included not meeting entry criteria (n = 13), withdrawal of consent (n = 5), and unstable medical conditions (n = 3). Although almost half of the participants (48%) had comorbid diseases such as hypercholesterolemia, cardiac arrhythmias, and osteoporosis, the prevalence of these conditions was similar among the three groups (51% in Group A, 46% in Group B, and 47% in Group C). Concomitant medications such as anticholinergics, anticonvulsants, antidepressants, and antipsychotics were not allowed during the course of this study. Stable use of cholinesterase inhibitors (donepezil), statins, or low-dose aspirin was allowed and the actual number of patients using these drugs was as follows: donepezil 29, statins 18, and aspirin 4 in Group A; donepezil 31, statins 21, and aspirin 4 in Group B; donepezil 34, statins 23, and aspirin 5 in Group C. There was no significant difference in the percentage of the use of these drugs among the three groups. The mean ± SE duration of donepezil usage was 2.0 ± 0.2 years (Group A), 2.2 ± 0.1 years (Group B), and 2.1 ± 0.2 years (Group C) and there was no significant difference among these data. Of 162 participants, 158 had a history of treatment with antihypertensive drugs prior to study enrollment and the actual number of patients under each treatment regimen was as follows: 13 diuretics, 6 β-blocker, 31 calcium-channel blocker other than nifedipine or nilvadipine, 1 no treatment in Group A; 16 diuretics, 7 β-blocker, 28 calcium-channel blocker other than nifedipine or nilvadipine, 2 no treatment in Group B; 15 diuretics, 9 β-blocker, 33 calcium-channel blocker other than nifedipine or nilvadipine, 1 no treatment in Group C. There were no significant differences in the percentages of the use of any drug among the three groups. All participants were prospectively followed up for 12 months.

The primary analysis was a comparison of the change in MMSE score between Group A and Group B or Group C using analysis of variance and analysis of covariance with the baseline MMSE score as a covariate. Only p values lower than 0.05 were regarded as significant. This study was approved by the Tohoku University Ethical Committee and informed consent was obtained from participants or their caregivers before the study.

Results.

During the follow-up period, all participants had a stable and comparable blood pressure under antihypertensive treatment (132 ± 4 [SE] mm Hg in Group A; 133 ± 2 mm Hg in Group B; 130 ± 3 mm Hg in Group C) and completed the study, except one in Group C who dropped out of the study due to hypotension.

The mean baseline MMSE values were 19.3 ± 0.5 (SE) in Group A; 20.7 ± 0.4 in Group B; and 20.5 ± 0.4 in Group C, and no differences were found among the three groups (p > 0.4) (figure). The mean 1-year decline in MMSE scores in the participants of Group A (0.6 ± 0.1, n = 51) was lower vs those in the participants of Group B (4.6 ± 0.3, n = 53, p = 0.0023) or Group C (4.9 ± 0.3, n = 57, p < 0.001) (see the figure).

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Figure. Baseline and end-point Mini-Mental State Examination (MMSE) scores are indicated in individuals of the brain-distributing angiotensin-converting enzyme (ACE) inhibitor group (Group A) (closed circles), non brain-distributing ACE inhibitor group (Group B) (open circles), or calcium channel blocker group (Group C) (closed triangles). There were no significant differences in the baseline MMSE scores among the three groups. The mean 1-year decline rate in MMSE scores in the participants of Group A was significantly lower compared with those in participants of Group B or Group C.

Discussion.

Treatment with brain-penetrating ACE inhibitors could slow the rate of cognitive decline in mild to moderate AD patients in comparison with other antihypertensive drugs. The mechanism of this effect is not known. The favorable effect might be due to the direct effects of brain-penetrating ACE inhibitors on RAS in the brain,1,2⇓ since no significant differences were found in the levels of blood pressure among the three groups. Another possible mechanism might be an increased level of brain substance P (SP) by ACE inhibitors.6 Increased SP can augment the activity of neprilysin, a major amyloid-β peptide degrading enzyme in the brain, and thus may favorably influence the course of AD.7

The limitation of this study is that the declining rate of MMSE scores in Group B or Group C was more pronounced compared with a previous study.4 We reanalyzed the patients in Group B or Group C who showed a rapid decline in MMSE scores (more than 6 points per year) and found that they had limited activities of daily living (ADL). However, there were no significant differences in the proportion of these frail AD patients with limited ADL among the three groups. If we exclude those patients who showed a rapid decline in MMSE scores in Group B or Group C from the analysis, the mean annual rate of decline in MMSE scores was 3.5 in Group B and 3.7 in Group C, which is comparable to previous studies. These results suggest that brain-penetrating ACE inhibitors might have a clinical benefit even in patients with limited ADL, who might have shown a rapid decline in MMSE scores if not assigned to these drugs.

Brain penetrating ACE inhibitors might have benefits not only for the prevention but also for the treatment of mild to moderate AD.