Curb Your Enthusiasm for ACE Inhibitors in Alzheimer Disease

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RESEARCH UPDATE

Centrally acting angiotensin-converting enzyme inhibitors (C-ACEIs) may reduce the risk of Alzheimer disease (AD) in persons who receive them for treatment of hypertension, and improvement in cognitive decline has been reported in patients with dementia. However, findings from a large, retrospective, observational study challenge the notion that C-ACEIs are therapeutic in patients with AD.¹Study design

The study was conducted by a multicenter team of British researchers who used data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre case registry, a large mental healthcare case registry that is often accessed for research studies. The research team sought to assess cognitive decline and survival after diagnosis of AD in patients receiving C-ACEIs, non-centrally acting ACEIs (NC-ACEIs), or neither. They compared the Mini-Mental State Examination (MMSE) scores of patients receiving C-ACEIs with those of patients receiving NC-ACEIs and patients who were not taking ACEIs at the time of AD diagnosis. Patients who were taking angiotensin-receptor blockers were excluded from the analysis as were patients who had fewer than 2 MMSE scores recorded within the 36 months after the date of AD diagnosis.

C-ACEIs were defined as perindopril, ramipril, trandolapril, captopril, fosinopril, and lisinopril. NC-ACEIs were defined as enalapril, imidapril, cilazapril, quinapril, and moexipril. The evaluable population consisted of 1207 patients receiving C-ACEIs, 143 receiving NC-ACEIs, and 3910 receiving neither. Mean age was 80 to 81 years, and the mean number of MMSE scores per patient was 4 to 5.

Results

A generalized additive model for location, scale, and shape (GAMLSS)-a statistical model that allows for a nonlinear and parametric approach to regression analysis-was used to “visualize” MMSE score trajectories, which were plotted through 36 months following AD diagnosis. GAMLSS trajectory plots for the first 9 months after AD diagnosis showed a robust increase in MMSE scores in patients receiving C-ACEIs-an increase of 0.72 points per year. An increase of 0.19 points per year was seen in patients who received no ACEIs, and a decrease of 0.61 points per year was seen in those taking NC-ACEIs.

However, no significant group differences in score trajectories from 9 to 36 months and no differences in survival among the study groups were seen. A similar downward slope was seen for all 3 study groups between the 9- to 36-month period. The researchers concluded that although an initial robust improvement in cognition was realized in patients receiving C-ACEIs, the agents do not provide sustained protection against cognitive decline and dementia progression.

Future directions

The study authors noted that reasons for the initial improvement might be either improvement of cerebral blood flow (as angiotensin II is a vasoconstrictor), suppression of inflammatory cytokines, or suppression of angiotensin II’s suppression of acetylcholine release. They surmised that given the short-lived nature of cognitive improvement, the third supposition, together with other factors yet to be elucidated, might be the most plausible, calling it the more “symptomatic” of the mechanisms described. Finally, the study authors note that additional research is needed to evaluate whether the short-term protective effect of C-ACEIs in patients with AD might have a broader therapeutic impact in terms of delayed dependency or functional outcomes.

References:

1. Fazal K, Perera G, Khondoker M, et al. Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer’s disease. BJPsych Open. 2017;3:158-164.