The Role of Apolipoprotein E in Alzheimer’s Disease

By Jungsu Kim, Jacob M Basak, D. Holtzman. Neuron, 2009

1,606 citations recorded by the source corpus.

The ε4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer’s disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, the manner in which apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Aβ aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE ε4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE. In addition, modulation of apoE protein levels and lipidation state by low-density lipoprotein (LDL) receptor family members and ATP-binding cassette transporter A1 (ABCA1) may be useful to exploit as future therapeutic targets.

Subfields: Computational Theory and Mathematics, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/99d5f72dcf5e74b20034e990bd45d1f4a574b4e6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Computational Theory and Mathematics

1. Rudolph E. Tanzi
2. G. Bu
3. Berislav Zlokovic
4. J. Herz
5. Zeinab Breijyeh
6. Rafik Karaman
7. D. Holtzman

In Pharmacology

1. G. Bu
2. J. Herz
3. D. Holtzman
4. Rudolph E. Tanzi
5. Berislav Zlokovic
6. E. Masliah
7. Zeinab Breijyeh
8. Rafik Karaman

In Physiology

1. D. Holtzman
2. G. Bu
3. Berislav Zlokovic
4. A. Goate
5. J. Herz
6. Rudolph E. Tanzi
7. John C. Morris
8. E. Karran

Citations in the corpus

• The Adverse Effects of Air Pollution on the Nervous System (2012, background): “The ApoE ε4 allele is known to contribute to a genetic predisposition for late-onset AD, although the mechanisms by which ApoE ε4 influences onset and progression of the disease are not well understood [101, 108].”
• Alzheimer's disease risk genes and mechanisms of disease pathogenesis (2014, neutral): “APOE binds to Aβ and influences the clearance of soluble Aβ and the Aβ aggregation (35,36).”
• The genetics of Alzheimer disease. (2012, background): “Thus, the two LOAD-associated mutations in ADAM10 would appear to be strong candidates for the first rare, highly penetrant pathogenic mutations to be genetically associated with late-onset AD (Kim et al. 2009).”
• Alzheimer’s Disease: The Challenge of the Second Century (2011, background): “In addition to expression in the liver, apoE is also produced at high levels within the CNS, where it is present in highdensity lipoprotein (HDL)–like lipoproteins secreted predominantly by astrocytes (121).”
• Human apoE isoforms differentially regulate brain amyloid-β peptide clearance (2011, neutral): “Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40).”
• Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders (2011, background): “Importantly, a recent longitudinal CBF study in neurologically normal individuals revealed that people bearing the apolipoprotein E (APOE) ɛ 4 allele — the major genetic risk factor for late-onset Alzheimer's diseas”
• Amyloid Precursor Protein Processing and Alzheimer’s Disease (2011, background): “It is appealing to think ApoE increases clearance or cellular uptake of Aβ via receptor-mediated binding, but the data are not yet clear on this issue (Kim et al. 2009).”
• The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics (2011, background): “, with APOE2, APOE3 and APOE4 being increasingly less effective at clearing amyloid-”
• Comprehensive Review on Alzheimer’s Disease: Causes and Treatment (2020, background): “The ApoEε4 allele is a strong risk factor for both EOAD and LOAD compared to ApoEε2 and ApoEε3 alleles that are associated with a lower risk and protective effect, respectively [58].”
• Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, positive): “Strong evidence suggests a major mechanism by which apoE influences AD and cerebral amyloid angiopathy (CAA) is via its effects on Ab metabolism (Kim et al. 2009a; Castellano et al. 2011).”