Introduction: Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer's disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) is an element of 4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-beta (A beta) plaques and an increase in the number of A beta-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer's patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) A beta 42 levels. Methods: The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF A beta 42 was measured. Results: ApoE is an element of 4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF A beta 42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF A beta 42, and thus the association was not due to increased impulsivity. Conclusions: These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to A beta 42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE is an element of 4 homocygotes.