Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions

Rebeck, G. William; Reiter, Julia; Strickland, Dudley K.; Hyman, Bradley T.

doi:10.1016/0896-6273(93)90070-8

Cited by 968 publications

(134 citation statements)

References 36 publications

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“…Whether APOE affects AD via an effect on Aβ is controversial. APOE genotype strongly affects the extent of amyloid deposition in patients (6), and genetically engineered animals expressing human APOE2 , APOE3 , and APOE4 have a similar rank order of amyloid burden as humans (7), consistent with the hypothesis that different APOE isoforms affect plaque initiation and growth. APOE variants have also been suggested to modify the amount of neurotoxic soluble oligomeric Aβ (8) and to differentially influence cerebrovascular integrity and Aβ efflux through the blood-brain barrier (BBB) (9, 10).…”

Section: Introductionmentioning

confidence: 53%

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Gene Transfer of Human Apoe Isoforms Results in Differential Modulation of Amyloid Deposition and Neurotoxicity in Mouse Brain

et al. 2013

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Inheritance of the ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor associated with the sporadic form of Alzheimer's disease (AD), whereas the rare APOE ε2 allele has the opposite effect. However, the mechanisms whereby APOE confers risk and protection remain uncertain. We used a gene transfer approach to bathe the cortex of amyloid plaque–bearing transgenic mice with virally expressed human APOE. We monitored amyloid-β (Aβ) with multiphoton imaging, in vivo microdialysis, and postmortem array tomography to study the kinetics of human APOE-mediated changes in Aβ-related neurotoxicity in a mouse model of AD. We observed that human APOE4 increased the concentrations of oligomeric Aβ within the interstitial fluid and exacerbated plaque deposition; the converse occurred after exposure to human APOE2. Peri-plaque synapse loss and dystrophic neurites were also worsened by APOE4 or attenuated by APOE2. Egress of Aβ from the central nervous system (CNS) into the plasma was diminished by APOE3 and APOE4 compared to APOE2, in accord with isoform-specific retention of Aβ in the CNS. Overall, our data show a differential effect of human APOE isoforms on amyloid deposition and clearance in transgenic mice and, more importantly, on Aβ-mediated synaptotoxicity. These results suggest that the APOE genetic risk is mediated by Aβ, and that therapeutic approaches aimed at decreasing APOE4, or increasing APOE2, may be beneficial in AD.

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Section: Introductionmentioning

confidence: 53%

“…Indeed, human APOE protein was present around amyloid deposits throughout the cortical mantle where APOE protein is known to accumulate (Fig. 1D) (6, 16). …”

Section: Resultsmentioning

confidence: 99%

Gene Transfer of Human Apoe Isoforms Results in Differential Modulation of Amyloid Deposition and Neurotoxicity in Mouse Brain

et al. 2013

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“…Initial histopathological studies investigating the relationship between amyloid plaques and APOE isoforms had demonstrated a positive correlation between plaque density and APOE ε4 allele dose. 37 To explain the difference in amyloid plaque load between APOE ε4+ and APOE ε4− patients, it is speculated that the Aβ deposition may have been ongoing for a longer time in APOE ε4+ patients. 20 This hypothesis was supported by data from studies in epidemiology and neuropathology, which demonstrated earlier onset of disease, or higher cerebral amyloid load in younger APOE ε4+ subjects with AD.…”

Section: Discussionmentioning

confidence: 99%

APOE genotype and neuroimaging markers of Alzheimer's disease: systematic review and meta-analysis

Liu

Wang

et al. 2014

Journal of Neurology, Neurosurgery & Psychiatry

128

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Objective We aimed to examine the association of apolipoprotein E (APOE) ε4 genotype with neuroimaging markers of Alzheimer’s disease: hippocampal volume, brain amyloid deposition and cerebral metabolism. Methods We performed a systematic review and meta-analysis of 14 cross-sectional studies identified in Pubmed from 1996 to 2014 (n=1628). The pooled standard mean difference (SMD) was used to estimate the association between APOE and hippocampal volume and amyloid deposition. Meta-analysis was performed using effect size signed differential mapping using coordinates extracted from clusters with statistically significant difference in cerebral metabolic rate for glucose between APOE ε4+ and ε4− groups. Results APOE ε4 carrier status was associated with atrophic hippocampal volume (pooled SMD: −0.47; 95% CI −0.82 to −0.13; p=0.007) and increased cerebral amyloid positron emission tomography tracer (pooled SMD: 0.62, 95% CI 0.27 to 0.98, p=0.0006). APOE ε4 was also associated with decreased cerebral metabolism, especially in right middle frontal gyrus. Conclusions APOE ε4 was associated with atrophic hippocampal volume in MRI markers, increased cerebral amyloid deposition and cerebral hypometabolism. Theses associations may indicate the potential role of the APOE gene in the pathophysiology of Alzheimer’s disease.

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“…In APP transgenic mice, APOE influences the amount and structure of intraparenchymal Aβ deposits in an isoform specific manner (38-41). Neuropathological and neuroimaging studies demonstrate that APOE ε4 carriers exhibit accelerated and more abundant Aβ deposition than APOE ε4 negative individuals (42-44). APOE εgenotype is also associated with CSF Aβ42 and tau levels (15, 16, 43).…”

Section: Cholesterol Metabolismmentioning

confidence: 99%

Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis

Karch¹,

Goate²

2015

Biological Psychiatry

1,069

845

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Here, we review the genetic risk factors for late onset Alzheimer's disease (AD) and their role in AD pathogenesis. Recent advances in our understanding of the human genome, namely technological advances in methods to analyze millions of polymorphisms in thousands of subjects, have revealed new genes associated with AD risk: ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4 RIN3, SORL1, ZCWPW1. Emerging technologies to analyze the entire genome in large datasets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathological features of AD. Together, understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.

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Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions

Cited by 968 publications

References 36 publications

Gene Transfer of Human Apoe Isoforms Results in Differential Modulation of Amyloid Deposition and Neurotoxicity in Mouse Brain

Gene Transfer of Human Apoe Isoforms Results in Differential Modulation of Amyloid Deposition and Neurotoxicity in Mouse Brain

APOE genotype and neuroimaging markers of Alzheimer's disease: systematic review and meta-analysis

Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis

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