Apolipoprotein E (ApoE) epsilon 4 is a well-documented risk factor for Alzheimer's disease (AD). Patients with AD show neuronal damage, particularly in the medial temporal lobe structures involved in memory processing. ApoE has been implicated in nerve regeneration following injury, and synaptogenesis in the hippocampus of experimental animals. Recent studies have shown an increased accumulation of beta A4 amyloid and an increased deficit in ACh-containing neurons in the brains of AD patients that are homozygous for ApoE epsilon 4 compared with those lacking epsilon 4. Furthermore, AD patients with two ApoE epsilon 4 alleles have more-severe loss in hippocampal volume in magnetic resonance imaging (MRI) scans, and more impairment in tests assessing delayed memory, than AD patients without the epsilon 4 allele, in spite of similar global severity of dementia. Minor changes in hippocampal MRI volumetry can also be detected in nondemented elderly, particularly in those with an epsilon 4/4 genotype. Data from a population-based study revealed that elderly subjects carrying the epsilon 4 allele had worse learning ability than those with the epsilon 2/2 or epsilon 2/3 phenotypes, whereas these groups did not differ in other cognitive domains. These data suggest that ApoE epsilon 4 might influence the magnitude of medial temporal lobe atrophy and memory impairment in AD and also in nondemented elderly.