Review: The renin-angiotensin-aldosterone system and Alzheimer's disease?

Abstract

Epidemiological studies from the last decade have begun to produce evidence that the perceived joint occurrence of vascular disease and Alzheimer's disease (AD), both common elderly disorders more often believed to occur by chance due to their high prevalence, may now actually have a more pathological significance. The following review discusses some of this evidence and the implications for cognitive decline and the development of AD and how a well-known cardiovascular risk factor gene, the apolipoprotein E (APOE) gene, plays a significant role in the molecular genetics of AD. It also introduces and discusses recent and compelling evidence for the involvement of another well-known cardiovascular risk factor gene, the angiotensin-converting enzyme (ACE1) gene, in the pathogenesis of AD. This role is suggested in terms of recent molecular genetic association evidence implicating the ACE1 insertion/deletion (indel) polymorphism, a more recent large haplotype study that greatly extends the ACE1 indel evidence and incorporates knowledge accrued from previous cardiovascular disease-focused ACE1 haplotype studies. Finally, this paper discusses very recent biological evidence that further supports a role for ACE1 and hypothesises a number of readily testable mechanisms by which the ACE1 enzyme and other components of the renin-angiotensinaldosterone system may be implicated in increased risk and/or the progression of AD.

Common variants of ACE contribute to variable age-at-onset of Alzheimer’s disease

“…This is reflected by a number of confirmatory genetic association studies, successive meta-analyses, a large haplotype study, and both in vitro and in vivo evidence of a role for the ACE enzyme in the degradation of Aβ, which is one of the primary adverse biological agents implicated in AD pathogenesis (Selkoe 1991(Selkoe , 2000Hardy 1997). Collectively, these data support the suggested role of the ACE enzyme and ACE variation in the development of AD (Kehoe 2003). In this study, we report our efforts to complement links between ACE variation and AD risk by assessing the AAO of disease.…”

Cerebral Hypoperfusion and the Energy Deficit in Alzheimer's Disease

“…These drugs improve cerebral perfusion in mild to moderate disease (19), and several studies found evidence of an association between cognitive response and cerebral blood flow (13,26,124). The potential for intervention in the renin-angiotensin system has been extensively reviewed (56)(57)(58)(59) and the effects on cognition and cerebral blood flow of losartan, an angiotensin receptor antagonist, are currently being tested in a multicentre UK clinical trial (115).…”

Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function

“…Central RAS is involved in the regulation of several physiological and behavioral processes including cognitive functions (Gard 2002;Wright and Harding 2011). Several studies have investigated the Alzheimer's disease (AD) related alterations in the brain RAS (Kehoe 2003;Kehoe et al 2009). Angiotensin-converting enzyme (ACE) activity and angiotensin type 1 (AT1) and angiotensin type 2 (AT2) [94] receptor expression have been found to be increased in AD brain suggesting an augmented brain RAS activity during the disease process (Savaskan et al 2001;Savaskan 2005).…”