Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population

doi:10.1016/S0304-3940(99)00827-7

Neuroscience Letters

Volume 277, Issue 1, 17 December 1999, Pages 65-67

https://doi.org/10.1016/S0304-3940(99)00827-7 Get rights and content

Abstract

We compared the distribution of an insertion (I)/deletion (D) polymorphism of the gene coding for the angiotensin-converting enzyme (ACE) in 133 Japanese sporadic Alzheimer disease (AD) patients with 257 controls. The association between AD and ACE genotypes or alleles was found to be significant. The frequency of II genotypes was 1.4 times higher in AD than controls, while that of DD genotypes was only 0.4 times as high. The altered distribution of ACE alleles in patients with AD appeared to be independent of apolipoprotein E.

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Cited by (71)

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury
2021, Biomedicine and Pharmacotherapy
Citation Excerpt :
In the central nervous system (CNS), both ACE and ACE2 have the ability to hydrolyze the amyloid-β (Aβ) peptide, which plays a key role in the pathogenesis of Alzheimer disease (AD), for review, see [63]. In the Japanese population, there is a significant association between the ACE genotype and AD [64]. This is explained by reduced plaque formation, the hallmark of AD, due to inhibition of Aβ aggregation by ACE [65].
The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-β, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.
Prognostic plasma protein panel for Aβ deposition in the brain in Alzheimer's disease
2019, Progress in Neurobiology
Citation Excerpt :
Increased ACE activity and adjusted ACE protein levels are found in the frontal cortex of AD, and the exposure of neuronal cells to oligomeric Aß in vitro increases ACE level and activity (Miners et al., 2009). The allelic genotype of ACE is significantly associated with AD; the ACE1 gene variant rs179975 is associated with elevated ACE levels in the plasma and reduced risk of AD (Kehoe et al., 1999), which have been shown in different ethnic populations (Hu et al., 1999). Therefore, changes in ACE seem to be tightly associated with AD pathogenesis.
Alzheimer’s disease (AD) is the most common age-associated dementia. Many studies have sought to predict cerebral amyloid deposition, the major pathological hallmark of AD, using body fluids such as blood or cerebral spinal fluid (CSF). The use of blood in diagnostic procedures is widespread in medicine; however, existing blood biomarkers for AD remain unreliable. We sought to discover blood biomarkers that discriminate Aβ deposition status in the brain. This study used 107 individuals who were cognitively normal (CN), 107 patients with mild cognitive impairment (MCI), and 40 AD patients with Pittsburg compound B positron emission tomography (PiB-PET) amyloid imaging data available. We found five plasma biomarker candidates via mass spectrometry (MS) based-proteomic analysis and validated these proteins using enzyme-linked immunosorbent assay (ELISA). Our integrated models were highly predictive of brain amyloid deposition, exhibiting 0.871 accuracy with 79% sensitivity and 84% specificity overall, and 0.836 accuracy with 68% sensitivity and 90% specificity in patients with MCI. These results indicated that a combination of proteomic-based blood proteins might be a possible biomarker set for predicting cerebral amyloid deposition.
The association between ACE I/D polymorphism and the risk of Alzheimer's disease in Lebanon
2018, Meta Gene
Citation Excerpt :
P = .0043) compared to DD genotype, suggesting that DD genotype confers a protective effect and is associated with longevity while allele I confers increased risk for AD (Yang et al., 2000). Another study replicating our positive association between the ACE I homozygote and AD was carried by Hu et al. (1999) on the Japanese population showing the frequency of II genotypes to be 1.4 times higher in AD than controls (Hu et al., 1999). In the German population, Kölsch and his colleagues also revealed the same finding, an increased risk of AD in ACE II genotype carriers (Kölsch et al., 2005).
The insertion/deletion (I/D) polymorphism in Angiotensin converting enzyme (ACE) has been extensively studied as candidate gene for Alzheimer's disease (AD). In this study, the possibility of such an association was investigated in 83 patients diagnosed with AD and 80 matched controls from Lebanese origin. ACE I/D genotypes differed significantly between affected individuals and controls. In addition, ACE I allele and female gender were positively associated with increased risk of AD (O.R = 1.7, P = .02 and O.R = 4.2, P = .001, respectively). Furthermore, ACE I/D interacted with gender to influence the risk of AD (OR = 1.67, P = .001). When stratified according to gender and AD status, ACE I/D distribution varied significantly between AD and controls in women (P = .05) but not in men (P = .47). In conclusion, our study suggests that ACE I allele and female gender are associated with increased risk of AD in the Lebanese population.
Association of insertion-deletion polymorphism of ACE gene and Alzheimer's disease in Egyptian patients
2014, Egyptian Journal of Medical Human Genetics
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.
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.
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.
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.
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.
Alteration of resting brain function by genetic variation in angiotensin converting enzyme in amnestic-type mild cognitive impairment of Chinese Han
2010, Behavioural Brain Research
Using a cross-sectional case–control study of amnestic-mild cognitive impairment (aMCI), we characterised the relationships among cognitive function, serum levels of angiotensin converting enzyme (ACE), brain activity, and ACE insertion or deletion (I/D) polymorphism. Forty-eight patients with aMCI and 36 well-matched normal controls were assessed by a comprehensive battery of standardized neuropsychological tests. In addition, regional homogeneity (ReHo) approaches were used to analyze blood oxygen level-dependent functional magnetic resonance imaging data on the resting state in all subjects, and genotyping of the serum ACE was measured in aMCI patients. The D carriers with aMCI patients were found to have markedly higher serum ACE levels than I homozygote carriers. Importantly, compared with the carried I homozygote group of patients with aMCI, the D carriers of aMCI patients were significantly impaired in the AVLT-delayed recall and had decreased ReHo over the bilateral precuneus, left middle occipital gyrus, right inferior parietal lobe, and right angular gyrus, whilst increased ReHo was found mainly in the left medial frontal gyrus, right paracentral lobe, and right anterior cingulate cortex. The findings indicated that ACE genotype was associated with episodic memory, serum levels of ACE, and resting-state brain activity in aMCI patients, and the findings of cognitive function and brain activity further suggests that the ACE D allele may have a specific role in semantic memory dysfunction and brain activity in aMCI.
Experimental approaches for altering the expression of Abeta-degrading enzymes
2023, Journal of Neurochemistry

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Neuroscience Letters

Abstract

References (20)

Angiotensin-converting enzyme gene polymorphism in systemic hypertension

Am. J. Cardiol.

Excitory action of angiotensins II and IV on hippocampal neuronal activity in urethane anesthitized rats

Regul. Pept.

Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI

J. Lipid. Res.

Anti-apoptotic action of angiotensin fragments to neuronal cells from angiotensinogen knock-out mice

Neurosci. Lett.

Angiotensin II- and IV-induced changes in cerebral blood flow. Roles of AT1, AT2, and AT4 receptor subtypes

Regul. Pept.

Relation between severity of coronary artery disease, left ventricular function and myocardial infarction, and influence of the ACE I/D gene polymorphism

Am. J. Cardiol.

Attenuation of scopolamine-induced spatial learning impairments by an angiotensin IV analog

Regul. Pept.

Genetic susceptibility to Alzheimer disease

Trends Gent.

Impaired blood-brain barrier function in angiotensinogen-deficient mice

Nat. Med.

Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease

Nat. Genet.

Cited by (71)

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

Prognostic plasma protein panel for Aβ deposition in the brain in Alzheimer's disease

The association between ACE I/D polymorphism and the risk of Alzheimer's disease in Lebanon

Association of insertion-deletion polymorphism of ACE gene and Alzheimer's disease in Egyptian patients

Alteration of resting brain function by genetic variation in angiotensin converting enzyme in amnestic-type mild cognitive impairment of Chinese Han

Experimental approaches for altering the expression of Abeta-degrading enzymes