Abstract and Introduction
Abstract
Objectives To assess whether angiotensin-converting enzyme inhibitor (ACE-I) treatment is associated with less cognitive decline in older adults with Alzheimer's disease (AD) than in those using other hypertensive or no drugs.
Design Four-year prospective multicenter cohort study with a biannual assessment.
Setting Memory clinics from 16 university hospitals in France.
Participants Community-dwelling older adults with mild to moderate AD (N = 616).
Measurements Participants were stratified into four groups according to type and duration of antihypertensive drug treatment. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE). Linear mixed-effects models were used to assess differences in decline in MMSE score between the four groups. Hypertension at each visit was included in the model.
Results Sixty-one participants had used ACE-Is continuously, 57 had used them intermittently, 189 had used other antihypertensive drugs, and 309 never used any antihypertensive drugs. Continuous ACE-Is users had a 4-year decline in MMSE of 6.4 ± 1.6 points (P < .001), intermittent ACE-Is users of 7.9 ± 1.1 points (P < .001), continuous or intermittent users of other antihypertensive drugs of 8.8 ± 0.7 points (P < .001), and never-users of 10.2 ± 0.6 points (P < .001). MMSE decline between the four groups was significantly different (adjusted P = .02). In subgroup analysis, the 118 (19.2%) participants who had continuously or intermittently used ACE-Is had a significant difference in 4-year MMSE decline from the 498 (80.8%) who had never used ACE-Is (7.5 ± 0.9 vs 9.7 ± 0.4; P = .03).
Conclusion The use of ACE-Is in older adults with AD is associated with a slower rate of cognitive decline independent of hypertension. Future research is needed to explore the role of ACE-Is in long-term AD progression.
Introduction
In Alzheimer's disease (AD), the reduction in beta-amyloid protein (Aβ) load is currently indicated as a potential therapeutic aim. The renin-angiotensin system (RAS), a well-recognized contributor to the pathogenesis of hypertension, has been increasingly studied as also being at the basis of AD. There is accumulating evidence that the brain has its own RAS, mediating several physiopathological brain functions. Findings from in vitro studies and in animal models have shown that angiotensin-converting enzymes (ACEs) may play an important role in metabolism of Aβ. In humans, several clinical trials have evaluated the benefits of ACE-inhibitors (ACE-Is) on cognition. Three found positive results in term of prevention of dementia or cognitive decline in adults without dementia, whereas others reported nonsignificant findings. In longitudinal observational studies, conflicting results have also been found. Furthermore, stabilization of cognitive function by ACE-Is has been reported in individuals with amnestic mild cognitive impairment.
The effect of antihypertensive therapy with ACE-Is on cognitive decline in individuals with AD is still unknown. Only a few studies have specifically examined the effect of ACE-Is on AD progression and have reported conflicting results. Brain-penetrating ACE-Is seem to offer more-beneficial cognitive effects in individuals with hypertension and AD than non-brain-distributed ACE-Is and calcium channel blockers. In support of this finding, an association between ACE-I exposure and better working memory in individuals with AD has been reported, although ACE-Is have been found to be ineffective in improving cognition in individuals with AD. Thus, the protective effect of ACE-Is in AD remains controversial because of conflicting results. Moreover, the existing observational and therapeutic clinical studies have had limited sample sizes and short follow-up.
It was hypothesized that ACE-Is would affect cognitive decline in older adults with AD over 4 years of follow-up. The aim of this study was to assess whether continuous or intermittent treatment with ACE-Is is associated with less cognitive decline in older adults with AD than in those using other hypertensive or no drugs.