Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer's disease

The Oxford Project to Investigate Memory and Ageing (OPTIMA), Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
American Journal of Epidemiology (Impact Factor: 5.23). 09/2005; 162(4):305-17. DOI: 10.1093/aje/kwi202
Source: PubMed


Apolipoprotein E ε4 (APOE*4) is the only fully established susceptibility allele for Alzheimer's disease. One of the most studied candidates is the insertion
(I)/deletion (D) polymorphism (indel) of the gene for angiotensin I-converting enzyme (ACE). This study aimed to clarify its association with Alzheimer's disease. The meta-analysis included 39 samples, comprising
6,037 cases of Alzheimer's disease and 12,099 controls, using mainly primary data. Potential interactions with gender, age,
ethnic group, and carrier status of the apolipoprotein E ε4 allele were all examined. D homozygotes were at reduced risk of Alzheimer's disease (odds ratio = 0.81, 95% confidence interval: 0.72, 0.90; corrected
p = 0.0004); I homozygotes showed no association with Alzheimer's disease, while heterozygotes were at increased risk. Although there were
clear differences among the three ethnic groups examined (North Europeans, South Caucasians, and East Asians), in all groups
D homozygotes were at reduced risk. These results confirm the association of the angiotensin I-converting enzyme indel with
Alzheimer's disease across diverse populations, although this is probably due to linkage disequilibrium with the true risk
factor. Further, in North Europeans, both association and Hardy-Weinberg analysis suggested partial heterosis, that is, an
increased risk for heterozygotes, due to a hidden interaction with another, as yet unknown, risk factor. This interaction
warrants further investigation.

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    • "Several studies have shown ACE to be capable of degrading Ab in vitro. Variations in ACE were associated with differences in CSF Ab level [22], and some animal data suggested that Ab level was increased by administration of ACE inhibitors . It is not well documented whether ACE inhibitor use in humans influences Ab accumulation. "
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    ABSTRACT: Introduction Alzheimer’s disease (AD) is a progressive, neurodegenerative disease. Many studies proposed an association of the insertion (I)/deletion (D) polymorphism (indel) in intron 16 of the gene for angiotensin I-converting enzyme (ACE) on chromosome 17q23 with Alzheimer’s disease. ACE indel and related haplotypes associated with AD risk have reduced plasma ACE whereas protective genotypes have elevated ACE. Object To investigate whether there is a correlation between polymorphisms of the ACE I/D locus gene and AD in Egyptian patients and to determine whether there is a difference in ACE activity in the plasma of clinically diagnosed AD patients. Methods Subjects of this study are 84 dementia patients diagnosed as having Alzheimer’s disease, 45 males and 39 females aged 65 ± 7 years from the Geriatric Department at Ain-Shams University Hospitals and 86 individuals as non dementia controls, 44 males and 42 females aged 63 ± 6 years. All subjects were genotyped for the common insertion/deletion polymorphisms for ACE gene locus, and ACE plasma activity assay was measured for AD patients. Results There was statistically significant difference in the frequency of the ACE insertion/deletion alleles between the cases and controls where the I allele distribution in AD cases and controls was 74% vs. 15%, and the I/I genotype frequency was 60% vs. 5%, respectively. They both reached a statistical significance range (I allele frequency: OR = 3.714, 95% CI 1.311–10.523, p < 0.01; I/I genotype frequency: OR = 3.18 95% CI 2.33–4.33, p < 0.01). But no significant difference in ACE plasma level was found between different genotypes in our AD patients. Conclusions Our present study supports the hypothesis of implication (I allele) of ACE gene polymorphism in the development of AD. On the other hand, we did not find significant difference in plasma ACE activities when compared with different studied genotypes.
    Preview · Article · Jun 2014 · Egyptian Journal of Medical Human Genetics
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    • "In the last decade, the role of the renin–angiotensin system (RAS) in the etiology of AD has received increasing attention. Inheritance of the I-allele – associated with lower plasma angiotensin-converting enzyme (ACE) levels [2] – was related to increased risk of AD [3,4], although these findings have not been supported by recent genome-wide association studies [5,6] and large haplotype studies [7]. Further, in vitro studies showed that ACE functions to degrade Aβ, and administration of ACE inhibitors promoted the accumulation of Aβ [8-10], while in vivo studies on various mouse models of AD showed indirect evidence that ACE can degrade Aβ (reviewed in [11]). "
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    ABSTRACT: Introduction Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau). Methods We included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid β1–42, tau and ptau (pg/ml) in CSF. Results Cross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively. Conclusions These results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD.
    Full-text · Article · May 2014 · Alzheimer's Research and Therapy
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    • "Literature review revealed the association between ACE I/D polymorphism and incidence of LOAD in 14 studies (Alvarez et al., 1999; Cheng et al., 2002; Crawford et al., 2000; Helbecque et al., 2009; Hu et al., 1999; Kehoe et al., 1999, 2003; Kölsch et al., 2005; Mattila et al., 2000; Narain et al., 2000; Ning et al., 2010; Richard et al., 2001; Wang et al. 2006; Wang et al., 2006) which shows positive association. However, there was no association between this polymorphism and LOAD in 20 studies (Buss et al., 2002; Camelo et al., 2004; Carbonell et al., 2003; Chapman et al., 1998; Cousin et al., 2009; Keikhaee et al., 2006; Lehmann et al., 2005; Lendon et al., 2002; Meng et al., 2006; Monastero et al., 2002; Myllykangas et al., 2000; Nacmias et al., 2007; Palumbo et al., 1999; Panza, 2002; Perry et al., 2001; Scacchi et al., 1998; Seripa et al., 2003; Wakutani et al., 2002; Wehr et al., 2006; Zuliani et al., 2001) showing negative association. According to several biochemical researches, Nterminal catalytic domain of ACE has the ability of degrading of amyloid-β (Aβ) peptide in vitro. "
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    ABSTRACT: Alzheimer's disease (AD) is a prevalent disorder and the most common cause of dementia in elderly populations. Genetic and environmental factors together play a role in developing late onset Alzheimer's disease (LOAD). According to the recent published papers, ACE is one of the candidate susceptibility genes for LOAD. In this study, allele and genotype frequencies for rs4291 and rs1799752 polymorphisms of ACE gene, for 100 Iranian patients, affected with AD and 100 healthy controls were compared using Chi-square test. No statistically significant differences were found in genotype and allele frequencies of rs4291 and rs1799752 polymorphisms between our LOAD patients and controls. The pair-wise haplotype analysis of rs4291 -240 A/T and rs1799752 Alu I/D polymorphisms were also performed, but no significant associations were identified.
    Full-text · Article · Apr 2012 · AFRICAN JOURNAL OF BIOTECHNOLOGY
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