Journal Article

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Kanekiyo, Takahisa, Bu, Guojun, Liu, Chia-Chen, Xu, Huaxi

2013

Overview

The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer disease (AD). Guojun Bu and colleagues describe the pathogenic links between Apo-E4 and neurodegeneration, including amyloid-β-dependent mechanisms and impairment of neurovascular function. The authors suggest potential strategies to target Apo-E, which could provide important additions to therapeutic options for AD. 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. Key Points The ε4 allele of the apolipo protein E ( APOE ) gene is the main genetic risk factor for Alzheimer disease (AD) APOE ε4 carriers have enhanced AD pathology, accelerated age-dependent cognitive decline and worse memory performance than do noncarriers Numerous structural and functional brain changes associated with AD pathogenesis are detected in APOE ε4 carriers before clinical symptoms become evident Apo-E affects amyloid-β (Aβ) clearance, aggregation and deposition in an isoform-dependent manner Apo-E4 also contributes to AD pathogenesis by Aβ-independent mechanisms that involve synaptic plasticity, cholesterol homeostasis, neurovascular functions, and neuroinflammation Apo-E-targeted AD therapy should focus on restoration of the physiological function of Apo-E through increased expression and lipidation, and inhibition of the detrimental effects of Apo-E4

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/420/2489/144 / 692/699/375/365/1283 / 692/700/565 / Age / Allelomorphism / Alzheimer Disease - epidemiology / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - psychology / Alzheimer Disease - therapy / Alzheimer's disease / Amino acids / Amyloid beta-Peptides - antagonists & inhibitors / Amyloid beta-Peptides - metabolism / Animals / Apolipoproteins / Apolipoproteins E - antagonists & inhibitors / Apolipoproteins E - genetics / Apolipoproteins E - metabolism / Apolipoproteins E - physiology / Brain / Brain - pathology / Brain Injuries - genetics / Brain Injuries - physiopathology / Cardiovascular disease / Cholesterol / Cognitive Dysfunction - pathology / Cognitive Dysfunction - psychology / Dementia / Dementia - genetics / Dementia - physiopathology / Dendritic Spines - physiology / Development and progression / Drug therapy / Genetic aspects / Health risk assessment / Homeostasis / Humans / Immunotherapy / Inflammation - genetics / Inflammation - pathology / Lipid Metabolism - genetics / Lipid Metabolism - physiology / Lipids / Medicine / Medicine & Public Health / Neurodegeneration / Neurogenesis - genetics / Neurogenesis - physiology / Neurology / Neuronal Plasticity - genetics / Neuronal Plasticity - physiology / Neurosciences / Pathogenesis / Physiological aspects / Predictive Value of Tests / review-article / Risk / Risk factors / tau Proteins - metabolism / Toxicity / Vascular Diseases - genetics / Vascular Diseases - physiopathology