BACKGROUNDAlzheimer's disease (AD) is a common fatal neurodegenerative disorder for which there is no effective treatment or cure. The biological basis of AD is poorly understood, although age and family history are two prominent risk factors.REVIEW SUMMARYEpidemiological and molecular evidence suggests that there are multiple etiologies for AD. Studies of the incidence and patterns of transmission in families demonstrate that relatives of affected individuals have an increased risk of developing AD compared with members of the general population. In the last few years, defects in the amyloid precursor protein gene and two novel genes dubbed presenilin 1 and 2, which cause familial (autosomal dominant) early-onset AD (<65 years) have been identified. These mutations account for approximately 80% of early-onset familial cases but less than 2% of all cases. In the vast majority of remaining cases, susceptibility is governed by a complex interaction of genes and environmental factors. Apolipoprotein E (APOE) is a cholesterol-binding protein that has three common isoforms encoded by alleles &epsis;2, &epsis;3, and &epsis;4. Association studies have revealed that APOE is an important susceptibility locus for sporadic and familial late-onset AD in most ethnic and racial groups. Risk of AD increases and age at onset decreases as a function of the dose of e4. APOE may interact with other genetic and environmental factors in modulating risk. The contribution of APOE genotype to risk of other dementias is controversial.CONCLUSIONPredictive and diagnostic testing for the rare causative mutations may be appropriate in some circumstances. However, the predictive value of APOE genotype on an individual basis is weak, and it is therefore not recommended as a predictive test. APOE may be an important adjunct for diagnosis in some situations. Many ethical, legal, and counseling concerns need to be addressed before genetic testing is offered outside carefully monitored research protocols.