Large Meta-Analysis Establishes the ACE Insertion-Deletion Polymorphism as a Marker of Alzheimer's Disease

Abstract

Apolipoprotein E epsilon4 (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 epsilon4 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.

Angiotensin-Converting Enzyme Converts Amyloid β-Protein 1–42 (Aβ1–42) to Aβ1–40, and Its Inhibition Enhances Brain Aβ Deposition

“…Numerous studies have shown that the I allele of ACE D/I polymorphism is associated with an increased risk of late-onset AD (Hu et al, 1999;Kehoe et al, 1999;Elkins et al, 2004;Lehmann et al, 2005) and that I polymorphism is associated with a decreased serum ACE level (Rigat et al, 1990). ACE activity in CSF from patients with a moderately severe senile dementia of the AD type has been shown to decrease to 41% of that in CSF from non-AD patients (Zubenko et al, 1985).…”

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

“…Specifically, the I allele was associated with an increased risk for AD, whereas the D allele was associated with protection (20,21). Of potential mechanistic relevance, inheritance of the D allele has been associated with increased plasma ACE levels (22).…”

Ancillary risk information and pharmacogenetic tests: social and policy implications

“…For example, Goldstein et al report that ACE (In-del variant) may predict decreased proteinuria in response to ACE inhibitors for renal disease; according to our review, this variant may also be associated with risk for Alzheimer disease. 9 However, this variant also has 21 'one positive study' results, suggesting unconfirmed but potential associated risk for 21 other diseases. Also, in the TNF gene variant G308A, the drug response is immunosuppressive therapy for aplastic anemia and sensitivity to the seizure medication carbamazepine.…”