Apolipoprotein E (APOE) alleles are currently the main known genetic determinants of Alzheimer disease risk, with APOE4 carriers showing increased risk of Alzheimer’s compared to the more common APOE3 allele. The relatively infrequent APOE2 allele carries decreased risk. The presence of APOE4 is also associated with increased risk of age-related cognitive decline during normal ageing. APOE-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to the amyloid-beta peptide, which is thought to initiate toxic events leading to synaptic dysfunction and neurodegeneration in Alzheimer Disease. APOE isoforms differentially regulate amyloid-beta aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. In this review, the authors describe the clinical and pathological features associated with different APOE isoforms. They also discuss amyloid-beta dependent and independent mechanisms that link APOE4 with Alzheimer risk, and possible treatment strategies.
Liu CC, Kanekiyo T, Xu H, Bu G: Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology [Epub ahead of print, Jan. 8, 2013; doi: 10.1038/nrneurol.2012.263 ].