Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy

By Chia-Chen Liu, T. Kanekiyo, Huaxi Xu, G. Bu. Nature Reviews Neurology, 2013

3,248 citations recorded by the source corpus.

Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E–lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

Subfields: Computational Theory and Mathematics, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/e7cefce9886a5c0a766e4065e160efc5e9746664

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Citations in the corpus

Variable Selection in Heterogeneous Datasets: A Truncated-rank Sparse Linear Mixed Model with Applications to Genome-wide Association Studies (2017, background): “The 4th discovered SNP resides within the region of AOPE, which is prominently believed to be cause Alzheimer’s disease [39].”
The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data (2014, neutral): “9 compared to the reference genotype of E3/3 (Liu et al. 2013).”
Neuroinflammation Induces Neurodegeneration (2016, background): “Studies have shown that APOE gene4 is associated with increased risk of AD pathogenesis [85].”
Inflammation as a central mechanism in Alzheimer's disease (2018, background): “regulation of lipid transport, and aid of injury repair within the brain, ApoE plays a role in glucose metabolism [276,277].”
Role of neuroinflammation in neurodegeneration development (2023, background): “A single amino acid difference between APOE3 and APOE4 leads to the changing of protein conformation which affects the binding of APOE with its receptors, lipids, and Aβ.(167) Carrying one APOE4 allele increases the risk of AD by 3–4 times, and carrying two alleles increases the risk by 9–15 times.”
Insulin Action in Brain Regulates Systemic Metabolism and Brain Function (2014, background): “The genetic variant ApoEe4 is the most common risk factor for late-onset AD, but the mechanism behind this observation remains largely unknown (97).”
β-Amyloid accumulation in the human brain after one night of sleep deprivation (2018, background): “SNPs of the APOE gene (rs7412 and rs429358) have been shown to influence brain glucose metabolism and ABB (67, 68).”