Apolipoprotein E (ApoE) 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 for cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. ApoE–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. ApoE 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 ApoE in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different ApoE isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link ApoE4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting ApoE.

PREFACEThe vast majority of Alzheimer's disease (AD) cases are late-onset and their development is likely influenced by both genetic and environmental risk factors. A strong genetic risk factor for lateonset AD is the presence of the ε4 allele of the apolipoprotein E (APOE) gene, which encodes a protein with crucial roles in cholesterol metabolism. Mounting evidence demonstrates that apoE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-β peptide and by directly regulating brain lipid metabolism and synaptic functions through apoE receptors. Emerging knowledge on the contribution of apoE to the pathophysiology of AD presents new opportunities for AD therapy. INTRODUCTIONAlzheimer's disease (AD) is the most common cause of dementia in the elderly. Extracellular amyloid plaques and intracellular neurofibrillary tangles are defining lesions in AD 1,2 . Mounting genetic and biochemical data support the hypothesis that amyloid-β(Aβ) accumulation and aggregation in the brain is an early and central event in the pathogenesis of AD 2,3 . Aβ is derived from sequential proteolytic processing of the amyloid precursor protein (APP) by β-and γ-secretases. Mutations associated with early-onset familial AD (FAD) are dominantly inherited and are found in the APP gene itself or in the genes of presenilin 1 (PSEN1) and PSEN2, whose products, together with nicastrin, APH-1 and PEN-2, are essential components of a multi-protein complex that is responsible for γ-secretase activity 4 . A common feature of most FAD mutations is that they increase the generation of Aβ peptides, or increase the proportion of the longer Aβ42 form, which has a higher tendency to aggregate and is more toxic than the shorter Aβ40 3 . Because γ-secretase cleavage of an increasingly recognized panel of substrates is important for synaptic function and neuronal survival, a loss-of-function hypothesis for PSEN mutations in AD pathogenesis has also been proposed 5 .FAD genetics and mouse models have shed light on early-onset AD pathogenesis, but the vast majority of AD cases occur late in life. The ε4 allele of the apolipoprotein E (APOE) gene is a major risk for late-onset AD (LOAD). This risk allele, discovered in 1993 by Strittmatter, Roses and colleagues 6,7 , has been validated in numerous genetic association studies (see AlzGene website at http://www.alzforum.org/res/com/gen/alzgene/default.asp). Although a gene on chromosome 19 had previously been implicated in LOAD risk, the Correspondence to: Guojun Bu, Department of Pediatrics, Washington University School of Medicine, CB 8208, 660 South Euclid Ave, St. Louis, MO 63110, USA, Phone: 314-286-2860, Fax: 314-286-2894 Competing interests statement The author declares no competing financial interest. NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2010 July 22. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript observation that apoE binds to Aβ in the cerebrospinal fluid (CSF) prompted the testing of APOE ...

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of lateonset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk, relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The list of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration, and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism, and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

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