This study by Eckman and colleagues elegantly shows how instructive pharmacology and genetics can be in understanding, and perhaps preventing, a complex disease. Using vasopeptidase inhibitors already used or in development for the clinic, the authors demonstrate that acute inhibition of NEP and/or ECE, but not ACE, results in elevation of cerebral and plasma Aβ levels. Furthermore, mice lacking expression of ACE in the brain are not burdened by elevated levels of murine Aβ, while, interestingly, in doubly NEP and ECE-1- or -2-deficient mice there is an additive accumulation of the peptide.

Where does this leave us in understanding the human disease? The findings on NEP and ECE inhibitors suggest caution when using these potential drugs in patients at risk for AD. The story with ACE may be more complicated. From a genetic perspective, there is a tremendous amount of work supporting the involvement of ACE in Alzheimer disease (AD), but less so for NEP and ECE. From clinical studies, reports of ACE inhibitor use have ranged from showing improvement to no effect on the course...  Read more

This study by Eckman and colleagues elegantly shows how instructive pharmacology and genetics can be in understanding, and perhaps preventing, a complex disease. Using vasopeptidase inhibitors already used or in development for the clinic, the authors demonstrate that acute inhibition of NEP and/or ECE, but not ACE, results in elevation of cerebral and plasma Aβ levels. Furthermore, mice lacking expression of ACE in the brain are not burdened by elevated levels of murine Aβ, while, interestingly, in doubly NEP and ECE-1- or -2-deficient mice there is an additive accumulation of the peptide.

Where does this leave us in understanding the human disease? The findings on NEP and ECE inhibitors suggest caution when using these potential drugs in patients at risk for AD. The story with ACE may be more complicated. From a genetic perspective, there is a tremendous amount of work supporting the involvement of ACE in Alzheimer disease (AD), but less so for NEP and ECE. From clinical studies, reports of ACE inhibitor use have ranged from showing improvement to no effect on the course of AD. A recent study reported finding that, on average, antihypertensive medications lowered the incidence of AD (Khachaturian et al., 2006). Interestingly, ACE inhibitors were the only drug class to actually elevate AD risk, though the comparison to control did not reach significance. Clearly, more questions must be answered to understand the role of ACE genetics and ACE inhibition in Alzheimer’s disease.

One limitation of animal modeling of human diseases is genetic homology. Murine Aβ differs from human at amino acid positions 5, 10, and 13 (with the proposed ACE cleavage site between residues 7 and 8), and murine ACE shares 83 percent amino acid identity with the human form. Human ACE has been shown to cleave human Aβ in several in vitro studies. However, it is unclear if murine ACE can cleave murine Aβ, if murine ACE can cleave human Aβ, or if human ACE can cleave murine Aβ. While other proteases have been shown to actively degrade Aβ in murine and human forms, it is unclear if ACE is an exception.

One possibility is that ACE is a minor Aβ-degrading protease, due to kinetic parameters, substrate competition, localization, or some other factor. How would ACE’s role in Aβ metabolism change as Aβ levels increase, plaques form, and other Aβ-degrading proteases become saturated? Could chronic ACE inhibition reveal a role for the protease in Aβ metabolism? Given that hypertension is a chronic condition, often treated with ACE inhibitors, and that Alzheimer disease develops over a lifetime, these questions warrant further investigation, and the work reported here takes many steps toward answering them.

References:
Khachaturian AS, Zandi PP, Lyketsos CG, Hayden KM, Skoog I, Norton MC, Tschanz JT, Mayer LS, Welsh-Bohmer KA, Breitner JC. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch Neurol. 2006 May;63(5):686-92. Epub 2006 Mar 13. Abstract

View all comments by Matthew Hemming

With this study, Eckman and colleagues have made an important contribution to our understanding of the possible roles of ACE and other Aβ-metabolizing enzymes in the pathogenesis of AD. It comes at a time of pressing need for in vivo data on the catabolism of Aβ and the mechanism of involvement of ACE in AD, following on from successive and consistently supportive meta-analyses of genetic association between ACE gene polymorphism and AD, and in vitro and cell-based overexpression studies demonstrating ACE-mediated degradation of Aβ.

The Eckman study provides interesting data and seems to argue against ACE being a significant player in vivo, and Matthew Hemming has also commented in Alzforum that “The story with ACE may be more complicated." Longitudinal and cross-sectional clinical studies have shown cognitive benefits from anti-hypertensive medications, including ACE inhibitors, but the picture remains unclear due to variability among these studies in the measurement and interpretation of cognitive performance and decline and the absence of neuropathological information. In...  Read more

With this study, Eckman and colleagues have made an important contribution to our understanding of the possible roles of ACE and other Aβ-metabolizing enzymes in the pathogenesis of AD. It comes at a time of pressing need for in vivo data on the catabolism of Aβ and the mechanism of involvement of ACE in AD, following on from successive and consistently supportive meta-analyses of genetic association between ACE gene polymorphism and AD, and in vitro and cell-based overexpression studies demonstrating ACE-mediated degradation of Aβ.

The Eckman study provides interesting data and seems to argue against ACE being a significant player in vivo, and Matthew Hemming has also commented in Alzforum that “The story with ACE may be more complicated." Longitudinal and cross-sectional clinical studies have shown cognitive benefits from anti-hypertensive medications, including ACE inhibitors, but the picture remains unclear due to variability among these studies in the measurement and interpretation of cognitive performance and decline and the absence of neuropathological information. In some studies, the long-term cognitive benefits of ACE inhibitors have been substantially less than those of other types of anti-hypertensive medications (e.g., Khachaturian et al., 2006). However, clinical trial data on patients with probable Alzheimer disease (Ohrui et al., 2004) and an observational study of patients with MCI (Rozzini et al., 2006) both suggest that the use of brain-penetrating ACE inhibitors is helpful in delaying cognitive decline in AD or stabilizing cognitive function in MCI.

The clinical picture as far as ACE is concerned is therefore far from clear, and in interpreting the findings of Eckman and colleagues we should be mindful of several limitations/implications of this study:

1. As Hemming has highlighted (and Eckman and colleagues acknowledge themselves), it would be premature to discount the possible effects of species differences in trying to extrapolate findings based upon interactions between murine forms of ACE and Aβ to the situation in humans.

2. The animals were young when tested. Aging affects a range of metabolic processes and compensatory pathways, including those involved in Aβ synthesis and clearance. Similar studies (as well as examination of other RAAS components) are needed on older animals.

3. A point the authors acknowledge is that their pharmacological modeling does not negate possible effects of chronic administration of ACE-Is on Aβ metabolism.

4. A fourth point and one partly suggested by Hemming is that ACE may be only “a minor Aβ-degrading protease, due to kinetic parameters, substrate competition, localization, or some other factor.” We would extend this point with respect to the localization of enzyme activity. The Eckman study did not examine the possible relevance of ACE-mediated Aβ degradation with respect to cerebrovascular Aβ (cerebral amyloid angiopathy). In animals this young there is little or no cerebrovascular Aβ deposition, and it is unlikely that differences in vascular Aβ or enzyme activity would have been detected in the crude homogenates analyzed in this study; however, even if ACE plays only a minor role in overall degradation of Aβ, the localization of this activity to blood vessels could have important clinical implications.

5. The final point we would make is that the findings in this study have implications that extend beyond Alzheimer disease. Considerable epidemiological evidence points to a relationship between hypertension, risk factors for atherosclerotic vascular disease and Alzheimer disease. It is important to consider the effects that intervention (such as enzyme inhibitors) directed at reducing the risk at one disease may have on the risk of others. We hope that this study will encourage more research on the metabolic processes and interactions that are involved in the development and progression of these overlapping diseases.

References:
Khachaturian AS, Zandi PP, Lyketsos CG, Hayden KM, Skoog I, Norton MC, Tschanz JT, Mayer LS, Welsh-Bohmer KA, Breitner JC. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch Neurol. 2006 May;63(5):686-92. Abstract

Ohrui T, Tomita N, Sato-Nakagawa T, et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology 2004;63(7):1324-5. Abstract

Rozzini L, Chilovi BV, Bertoletti E, et al. Angiotensin converting enzyme (ACE) inhibitors modulate the rate of progression of amnestic mild cognitive impairment. Int J Geriatr Psychiatry 2006;21(6):550-5. Abstract

View all comments by Patrick Kehoe
View all comments by Seth Love

This is a well-done paper; it emphasizes the need for meta-analyses to decipher relevant from irrelevant results in genetically complex diseases. Readers of this paper may also be interested in the continuously updated meta-analysis on the Alzforum's AD genetic database AlzGene.

View all comments by Lars Bertram