Levels of Angiotensin-Converting Enzyme and Apolipoproteins Are Associated with Alzheimer’s Disease and Cardiovascular Diseases

Angiotensin-converting enzyme-1 (ACE1) and apolipoproteins (APOs) may play important roles in the development of Alzheimer’s disease (AD) and cardiovascular diseases (CVDs). This study aimed to examine the associations of AD, CVD, and endocrine-metabolic diseases (EMDs) with the levels of ACE1 and 9 APO proteins (ApoAI, ApoAII, ApoAIV, ApoB, ApoCI, ApoCIII, ApoD, ApoE, and ApoH). Non-Hispanic white individuals including 109 patients with AD, 356 mild cognitive impairment (MCI), 373 CVD, 198 EMD and controls were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Multivariable general linear model (GLM) was used to examine the associations. ApoE ε4 allele was associated with AD, as well as ApoAIV, ApoB and ApoE proteins, but not associated with CVD and EMD. Both AD and CVD were associated with levels of ACE1, ApoB, and ApoH proteins. AD, MCI and EMD were associated with levels of ACE1, ApoAII, and ApoE proteins. This is the first study to report associations of ACE1 and several APO proteins with AD, MCI, CVD and EMD, respectively, including upregulated and downregulated protein levels. In conclusion, as specific or shared biomarkers, the levels of ACE1 and APO proteins are implicated for AD, CVD, EMD and ApoE ε4 allele. Further studies are required for validation to establish reliable biomarkers for these health conditions.

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Total ApoE and ApoE4 Isoform Assays in an Alzheimer's Disease Case-control Study by Targeted Mass Spectrometry (n = 669): A Pilot Assay for Methionine-containing Proteotypic Peptides

Molecular & Cellular Proteomics ◽

10.1074/mcp.m112.018861 ◽

2012 ◽

Vol 11 (11) ◽

pp. 1389-1403 ◽

Cited By ~ 53

Author(s):

Romain Simon ◽

Marion Girod ◽

Catherine Fonbonne ◽

Arnaud Salvador ◽

Yohann Clément ◽

...

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Case Control Study ◽

Case Control ◽

Performic Acid ◽

Protein Levels ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Control Study

Allelic polymorphism of the apolipoprotein E (ApoE) gene (ApoE ε2, ApoE ε3 and ApoE ε4 alleles) gives rise to three protein isoforms (ApoE2, ApoE3 and ApoE4) that differ by 1 or 2 amino acids. Inheritance of the ApoE ε4 allele is a risk factor for developing Alzheimer's disease (AD). The potential diagnostic value of ApoE protein levels in biological fluids (i.e. cerebrospinal fluid, plasma and serum) for distinguishing between AD patients and healthy elderly subjects is subject to great controversy. Although a recent study reported subnormal total ApoE and ApoE4 levels in the plasma of AD patients, other studies have found normal or even elevated protein levels (versus controls). Because all previously reported assays were based on immunoenzymatic techniques, we decided to develop an orthogonal assay based on targeted mass spectrometry by tracking (i) a proteotypic peptide common to all ApoE isoforms and (ii) a peptide that is specific for the ε4 allele. After trypsin digestion, the ApoE4-specific peptide contains an oxidation-prone methionine residue. The endogenous methionine oxidation level was evaluated in a small cohort (n = 68) of heterozygous ε3ε4 carriers containing both healthy controls and AD patients. As expected, the proportion of oxidized residues varied from 0 to 10%, with an average of 5%. We therefore developed a standardized strategy for the unbiased, absolute quantification of ApoE4, based on performic acid oxidization of methionine. Once the sample workflow had been thoroughly validated, it was applied to the concomitant quantification of total ApoE and ApoE4 isoform in a large case-control study (n = 669). The final measurements were consistent with most previously reported ApoE concentration values and confirm the influence of the different alleles on the protein expression level. Our results illustrate (i) the reliability of selected reaction monitoring-based assays and (ii) the value of the oxidization step for unbiased monitoring of methionine-containing proteotypic peptides. Furthermore, a statistical analysis indicated that neither total ApoE and ApoE4 levels nor the ApoE/ApoE4 ratio correlated with the diagnosis of AD. These findings reinforce the conclusions of previous studies in which plasma ApoE levels had no obvious clinical significance.

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Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease

Current Gene Therapy ◽

10.2174/1566523220666201123112822 ◽

2020 ◽

Vol 20 ◽

Author(s):

Md. Sahab Uddin ◽

Sharifa Hasana ◽

Md. Farhad Hossain ◽

Md. Siddiqul Islam ◽

Tapan Behl ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Massively Parallel Sequencing ◽

Late Onset ◽

Current Knowledge ◽

The Elderly ◽

Apoe Ε4 ◽

Sequencing Technologies ◽

Genetic Components ◽

Ε4 Allele

: Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic components. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood with three genes variants such as APP, PSEN1, and PSEN2 leading to disease. On the other hand, some common alleles including APOE are effectively associated with LOAD identified but the genetics of LOAD is not clear to date. It has been accounted that about 5% to 10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease- triggering genes yet. Although several genes have been identified through using the technology of next-generation sequencing in EOAD families including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants were identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers live into their 90s that propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetics facets which will assist to understand the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article based on current knowledge represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism which might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.

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Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

Current Alzheimer Research ◽

10.2174/1567205014666171016101816 ◽

2018 ◽

Vol 15 (4) ◽

pp. 386-398 ◽

Cited By ~ 22

Author(s):

Fabricio Ferreira de Oliveira ◽

Elizabeth Suchi Chen ◽

Marilia Cardoso Smith ◽

Paulo Henrique Ferreira Bertolucci

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Angiotensin Converting Enzyme ◽

Cognitive Decline ◽

Enzyme Inhibitors ◽

Late Onset ◽

Amyloid Β ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

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A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.006420 ◽

2019 ◽

Vol 294 (25) ◽

pp. 9760-9770 ◽

Cited By ~ 5

Author(s):

Shuyu Liu ◽

Fujiko Ando ◽

Yu Fujita ◽

Junjun Liu ◽

Tomoji Maeda ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Angiotensin Converting Enzyme ◽

Amyloid Precursor Protein ◽

Ace Inhibitors ◽

Ace Inhibitor ◽

Precursor Protein ◽

Causative Role ◽

Converting Enzyme ◽

Clinical Dose

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/− mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

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Decline in verbal memory during preclinical Alzheimer's disease: Examination of the effect of APOE genotype

Journal of the International Neuropsychological Society ◽

10.1017/s1355617702870096 ◽

2002 ◽

Vol 8 (7) ◽

pp. 943-955 ◽

Cited By ~ 65

Author(s):

KELLY L. LANGE ◽

MARK W. BONDI ◽

DAVID P. SALMON ◽

DOUGLAS GALASKO ◽

DEAN C. DELIS ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Episodic Memory ◽

Verbal Memory ◽

Verbal Learning ◽

Apoe Genotype ◽

Apoe Ε4 ◽

Dementia Syndrome ◽

Ε4 Allele

A subtle decline in episodic memory often occurs prior to the emergence of the full dementia syndrome in nondemented older adults who develop Alzheimer's disease (AD). The APOE-ε4 genotype may engender a more virulent form of AD that hastens this decline. To examine this possibility, we compared the rate of decline in episodic memory during the preclinical phase of AD in individuals with or without at least one APOE ε4 allele. Nondemented normal control (NC; n = 84) participants, nondemented older adults who subsequently developed dementia within 1 or 2 years (i.e., preclinical AD; n = 20), and patients with mild AD (n = 53) were examined with 2 commonly employed tests of episodic memory, the Logical Memory subtest of the Wechsler Memory Scale–Revised and the California Verbal Learning Test. Results revealed a precipitous decline in verbal memory abilities 1 to 2 years prior to the onset of the dementia syndrome, but there was little effect of APOE genotype on the rate of this memory decline. The presence of an APOE-ε4 allele, however, did have a differential effect on the sensitivity of the 2 types of memory tests for tracking progression and made an independent contribution to the prediction of conversion to AD. (JINS, 2002, 8, 943–955.)

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Interplay between the APOE Genotype and Possible Plasma Biomarkers in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205015666180601090533 ◽

2018 ◽

Vol 15 (10) ◽

pp. 938-950 ◽

Cited By ~ 4

Author(s):

Martina Zverova ◽

Eva Kitzlerova ◽

Zdenek Fisar ◽

Roman Jirak ◽

Jana Hroudova ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Apoe Genotype ◽

Plasma Biomarkers ◽

Plasma Melatonin ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Severity Of Dementia

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis and a common occurrence of comorbid diseases such as depression. It is accepted that the presence of the ε4 allele of the gene that encodes apolipoprotein E (APOE) is the strongest genetic risk factor for the development of sporadic AD. Melatonin, cortisol, homocysteine, and prolactin are presumed to be risk factors or biomarkers for stress- and age-related disorders. Objective: The interplay between the APOE genotype and plasma biomarkers was examined in patients with AD presenting with or without depression to contribute to understanding the interdependence of various molecular mechanisms in the pathophysiology of AD. Method: The APOE genotype and morning plasma melatonin, cortisol, homocysteine, and prolactin concentrations were measured in 85 patients with AD and 44 elderly controls. Results: A significant association between AD and the allele (ε4) or genotype (ε3/ε4 or ε4/ε4) frequencies of APOE was confirmed. Plasma homocysteine and cortisol levels were significantly increased in patients with AD compared to those in controls, independent of the presence of comorbid depressive symptoms or the severity of dementia. Significantly lower plasma melatonin concentration was found in patients with AD but not in controls, who were noncarriers of the APOE ε4 allele, regardless of the presence of depression or the severity of dementia in AD. Conclusion: Our findings indicate the existence of a little-known specific APOE-mediated mechanism that increases the plasma melatonin level in a subgroup of patients with AD who are carriers of the APOE ε4 allele.

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APOE-ε4 polymorphism and cognitive deficit among the elderly population of Fernando de Noronha

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2008000300002 ◽

2008 ◽

Vol 66 (2b) ◽

pp. 298-302 ◽

Cited By ~ 3

Author(s):

Anália Nusya Garcia ◽

Helker Albuquerque da Silva ◽

Renan Carlos Silva ◽

Eliane Maria Medeiros Leal ◽

Lorena Rodrigues ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Elderly Population ◽

Cognitive Deficit ◽

The Elderly ◽

Clock Drawing Test ◽

Apoe Ε4 ◽

Pcr Rflp ◽

Fernando De Noronha ◽

Ε4 Allele

BACKGROUND: Polymorphism of the gene for apolipoprotein E (APOE) is an important risk factor for the development of Alzheimer's disease. The ε4 allele of the APOE gene has been linked with a number of neuropsychiatric illnesses, and also with stress and depression among geriatric populations. OBJECTIVE: To identify APOE-ε4 polymorphism and correlate this with cognitive deficit among the elderly population of the island of Fernando de Noronha. METHOD: Neuropsychiatric tests (mini-mental state examination, verbal fluency test and clock drawing test) were applied to 52 elderly people without Alzheimer's disease. DNA was isolated from peripheral blood and genotyping of APOE was done by the PCR-RFLP method. RESULTS: 87% of the elderly population (mean age 69.6±7.0) had cognitive deficit. CONCLUSION: The observed frequency of the ε4 allele was 10%, but the correlation between the presence of ε4 and cognitive deficit in this population was not statistically significant.

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