Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

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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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Reduced Hippocampal Insulin-Degrading Enzyme in Late-Onset Alzheimer's Disease Is Associated with the Apolipoprotein E-ε4 Allele

American Journal Of Pathology ◽

10.1016/s0002-9440(10)63822-9 ◽

2003 ◽

Vol 162 (1) ◽

pp. 313-319 ◽

Cited By ~ 213

Author(s):

David G. Cook ◽

James B. Leverenz ◽

Pamela J. McMillan ◽

J. Jacob Kulstad ◽

Sasha Ericksen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Late Onset ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Ε4 Allele

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The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions

Neuronal Signaling ◽

10.1042/ns20180203 ◽

2019 ◽

Vol 3 (2) ◽

Cited By ~ 2

Author(s):

Holly C. Hunsberger ◽

Priyanka D. Pinky ◽

Warren Smith ◽

Vishnu Suppiramaniam ◽

Miranda N. Reed

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synapse Formation ◽

Late Onset ◽

Therapeutic Interventions ◽

Memory Decline ◽

Current Therapies ◽

Ε4 Allele ◽

The Impact

Abstract Alzheimer’s disease (AD) is the leading cause of dementia affecting almost 50 million people worldwide. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous APOE4 carriers being approximately 15-times more likely to develop the disease. With 25% of the population being APOE4 carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial. Though the exact mechanism by which ε4 allele increases the risk for AD is unknown, the processes mediated by APOE, including cholesterol transport, synapse formation, modulation of neurite outgrowth, synaptic plasticity, destabilization of microtubules, and β-amyloid clearance, suggest potential therapeutic targets. This review will summarize the impact of APOE on neurons and neuronal signaling, the interactions between APOE and AD pathology, and the association with memory decline. We will then describe current treatments targeting APOE4, complications associated with the current therapies, and suggestions for future areas of research and treatment.

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Confirmation of the 4 allele of the apolipoprotein E gene as a risk factor for late-onset Alzheimer's disease

Neurology ◽

10.1212/wnl.44.2.342 ◽

1994 ◽

Vol 44 (2) ◽

pp. 342-342 ◽

Cited By ~ 72

Author(s):

T. Brousseau ◽

S. Legrain ◽

C. Berr ◽

V. Gourlet ◽

O. Vidal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Apolipoprotein E ◽

Late Onset ◽

E Gene ◽

Apolipoprotein E Gene

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Apolipoprotein E allele 4 is not a sufficient or a necessary predictor of the development of Mild Cognitive Impairment

European Psychiatry ◽

10.1016/j.eurpsy.2009.02.009 ◽

2010 ◽

Vol 25 (1) ◽

pp. 15-18 ◽

Cited By ~ 9

Author(s):

R. Heun ◽

U. Gühne ◽

T. Luck ◽

M.C. Angermeyer ◽

U. Ueberham ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Apolipoprotein E ◽

Target Population ◽

Population Based ◽

Initial Development ◽

Apoe Ε4 ◽

Ε4 Allele

AbstractThe presence of Mild Cognitive Impairment (MCI) and of an apolipoprotein E (apoE) ε4 allele both predict the development of Alzheimer's disease. However, the extent to which this allele also predicts the development of MCI is unclear even though MCI is an early transitional stage in the development of Alzheimer's disease. The present study investigates the prevalence of the apoE ε4 allele in incipient MCI. Participants were recruited from the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). All subjects who were initially cognitively healthy, i.e. did not meet MCI criteria described by Petersen [Petersen RC. Mild cognitive impairment. J Intern Med 2004; 256(3): 183–94], and whose apoE status could be determined were followed-up. After 4.5 years, 15.5% of the cognitively healthy target population had developed MCI. The frequencies of the apoE ε4 genotype did not differ between individuals with incipient MCI (12.9%) and individuals who remained cognitively healthy during the study (18.4%, p > 0.5). Consequently, the apoE ε4 genotype is not a necessary or sufficient risk factor for MCI. Further studies need to investigate the influence of the whole range of genetic and environmental risk factors on the course of Alzheimer's disease including the initial development of MCI and the later conversion to Alzheimer's disease.

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Genetic and epigenetic study of an Alzheimer’s disease family with monozygotic triplets

Brain ◽

10.1093/brain/awz289 ◽

2019 ◽

Vol 142 (11) ◽

pp. 3375-3381 ◽

Cited By ~ 1

Author(s):

Ming Zhang ◽

Allison A Dilliott ◽

Roaa Khallaf ◽

John F Robinson ◽

Robert A Hegele ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Late Onset ◽

Accelerated Ageing ◽

Disease Phenotypes ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Disease Family

Zhang, Dilliott et al. examine a unique family with early- and late-onset Alzheimer’s disease phenotypes, as well as disease-discordant monozygotic triplets. The triplets and the patient with early-onset disease are carriers of the APOE ε4-allele plus rare substitutions in other genes. Epigenetic analyses suggest accelerated ageing in the early-onset patient.

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