A proportion of cases of Alzheimer disease show familial aggregation with a pattern of vertical transmission compatible with autosomal dominant inheritance. Isolation of the genetic defect causing this form of Alzheimer disease, which may elucidate the biochemical mechanisms underlying the pathogenesis of the Alzheimer disease phenotype, can theoretically be achieved by first defining the chromosomal location of the disease gene(s) by classical genetic linkage studies in large families segregating this disorder. Subsequently, other cloning strategies can be applied to isolate the disease gene from the chromosomal region showing tight linkage to the disease phenotype. This paper reports some recent results of such studies, and discusses some of the potential confounding events which must be considered when approaching inherited neuropsychiatric disorders using these strategies.