Apolipoprotein E in Alzheimer's disease and other neurological disorders

Abstract

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.

Figure 1

A large body of evidence suggests that the dominant effect of human apoE isoforms on AD risk is to shift the onset of disease via alterations in the probability of amyloid deposition, likely during the preclinical, asymptomatic phase. Consistent with this hypothesis, individuals appear to accumulate amyloid in the order ε4 > ε3 > ε2, well before AD clinical symptomology becomes manifest (Figure adapted from Holtzman, DM 2008 Nature, 454(7203):418–20).