Elsevier

The Lancet Neurology

Volume 10, Issue 3, March 2011, Pages 241-252
The Lancet Neurology

Review
Apolipoprotein E in Alzheimer's disease and other neurological disorders

https://doi.org/10.1016/S1474-4422(10)70325-2Get rights and content

Summary

Apolipoprotein E (APOE) is a 299-aminoacid protein encoded by the APOE gene. Three common polymorphisms in the APOE gene, ɛ2, ɛ3, and ɛ4, result in a single aminoacid change in the APOE protein. APOE ɛ2, ɛ3, and ɛ4 alleles strongly alter, in a dose-dependent manner, the likelihood of developing Alzheimer's disease and cerebral amyloid angiopathy. In particular, APOE ɛ4 is associated with increased risk for Alzheimer's disease whereas APOE ɛ2 is associated with decreased risk. The effects of APOE genotype on risk of these diseases are likely to be mediated by differential effects of APOE on amyloid-β accumulation in the brain and its vasculature. Response to treatment for Alzheimer's disease might differ according to APOE genotype. Because convincing evidence ties the APOE genotype to risk of Alzheimer's disease and cerebral amyloid angiopathy, APOE has been studied in other neurological diseases. APOE ɛ4 is associated with poor outcome after traumatic brain injury and brain haemorrhage, although the mechanisms underlying these associations are unclear. The possibility that APOE has a role in these and other neurological diseases has been of great interest, but convincing associations have not yet emerged.

Introduction

With few efficacious treatment options available, management of many neurological disorders presents clinicians with substantial challenges, while health-care systems are burdened with enormous strain. Understanding the environmental and genetic components that modulate risks and outcomes of neurological disease could provide useful information about management of these devastating disorders. After a series of landmark studies1, 2, 3, 4, 5 identifying a strong association between presence of the apolipoprotein E (APOE) ɛ4 allele and increased risk of Alzheimer's disease (AD) and decreased age of onset, as well as the protective role of APOE ɛ2, numerous studies have investigated putative associations of APOE genotype with risk or progression of various neurological disorders. Because of the various proposed roles of APOE in amyloid-β metabolism, CNS lipid homoeostasis, synaptic activity, response to cellular injury, and neuroinflammation, these investigations were hypothesised to show strong associations with several diseases. However, so far, evidence for an association between APOE genotype and disease risk and age of onset remains the most compelling for AD and cerebral amyloid angiopathy (CAA). APOE is believed to be linked to risk of these two diseases through isoform-dependent modulation of amyloid-β accumulation. Associations of APOE with outcomes after traumatic brain injury (TBI) or risk of Down's syndrome-associated dementia are also postulated to be, in part, mediated through isoform-dependent modulation of amyloid-β accumulation. Associations between APOE genotype and stroke, vascular dementia, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and other disorders have been suggested, but more research is needed to establish whether APOE has a role in these disorders. In this Review, we aim to assess evidence for associations of APOE genotype with risk and outcomes for various neurological diseases, with particular attention to AD and CAA, for which evidence of an association is strong (table). The many proposed roles of APOE in the nervous system are a challenge to understanding the involvement of this protein in the pathogenesis of neurological diseases and implications for treatment strategies. Here, we also assess differences in treatment response according to APOE status in clinical trials of AD.

Section snippets

Physiological function of APOE

Human APOE is a lipoprotein of 299 aminoacids that is expressed in many organs, with the highest expression in the liver followed by the brain.129 APOE exists mainly as a component of lipoprotein complexes along with other apolipoproteins and proteins in plasma and CSF.129 In humans, there are three major polymorphic forms of APOE: APOE2 (Cys112, Cys158), APOE3 (Cys112, Arg158), and APOE4 (Arg112, Arg158).130 Aminoacid differences at these positions are crucial as they alter the charge and

Alzheimer's disease

AD is a devastating neurodegenerative disease affecting about 26 million people worldwide.136 The disease is pathologically defined by extracellular accumulation of amyloid β, intracellular accumulation of tau, neuronal and synaptic loss, brain atrophy, and inflammation.6 Mutations in three genes, APP, PS1, and PS2, cause rare forms of autosomal dominant familial AD with clinical onset typically between the ages of 30–60 years.6 Several susceptibility genes have also been implicated in AD risk,

Traumatic brain injury

Results published over the past two decades have suggested a link between TBI and risk of AD.49, 50, 51 Several groups have reported a strongly increased risk of AD in patients with TBI who have an APOE ɛ4 allele (table).52, 53 One proposed mechanism for the increased development of dementia in patients with TBI is that brain trauma precipitates amyloid-β deposition, which is supported by the increased frequency of amyloid-β deposition identified in post-mortem cortical extracts from patients

Conclusions

Accumulating evidence suggests a central role for APOE in the modulation of processes of neurodegeneration, especially in AD and CAA. A large body of evidence has identified APOE ɛ4 as a major susceptibility factor and modulator of age at onset of AD, whereas APOE ɛ2 seems to confer protection (table). A convincing body of published work suggests that APOE genotype modulates risk of AD largely via amyloid β, probably through isoform-dependent effects on aggregation or clearance from the brain

Search strategy and selection criteria

References for this Review were identified through searches of PubMed up to December, 2010, with the search terms “APOE AND neurological disorders”, “APOE AND Alzheimer's disease”, “APOE AND drug AND Alzheimer's disease”, “APOE AND cerebral amyloid angiopathy”, “APOE AND traumatic brain injury”, “APOE AND stroke”, “APOE AND Down's syndrome”, “APOE AND vascular dementia”, “APOE AND Lewy body dementia”, “APOE AND inclusion-body myositis”, “APOE AND Creutzfeldt-Jakob disease”, “APOE AND

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