Apolipoprotein E (APOE, gene; ApoE, protein) is the major genetic susceptibility locus for the common forms of Alzheimer's disease (AD). There are three common polymorphisms in the population: epsilon 2, epsilon 3, and epsilon 4. The inheritance of each dose of epsilon 4 increases the risk and lowers the age of onset distribution for AD; epsilon 2 lowers the risk and increases the age of onset distribution. APOE-epsilon 4 has a high positive predictive value for AD, and is clinically useful as an adjunct in the early diagnosis of cognitively impaired patients. The APOE alleles have also been associated with risk of AD with head injury, intraneuronal localization of ApoE in animal stroke models, recovery of function after intracerebral hemorrhage, and recovery of psychological parameters after general cardiac anesthesia. A multifunctional role of ApoE in the brain implicates isoform-specific differences in interactions with several brain proteins including A beta, tau, and MAP-2. Intraneuronal ApoE is increased temporally and in relevant neurons in AD as a function of APOE genotype. Decreased glucose metabolism can be demonstrated by PET imaging in subjects two decades before the median age of onset as a function of APOE genotype. ApoE isoforms may also have different effects as antioxidants. The risk of stroke and vascular dementia has not been confirmed in neuropathological series to be related to specific APOE genotypes.