Alzheimer's disease: Genetic studies and transgenic models

Recent advances in a variety of areas of research, particularly in genetics and in transgenic (Tg)/gene targeting approaches, have had a substantial i mpact on our understanding of Alzheimer's disease (AD) and related disorder s. After briefly reviewing the progress that has been made in diagnostic as sessments of patients with senile dementia and in investigations of the neu ropathology of AD, we discuss some of the genes/proteins that are causative or risk factors for this disease, including those encoding amyloid precurs or protein, presenilin 1 and 2, and apolipoprotein E. In addition, we comme nt on several potential new candidate loci/genes. Subsequently, we review s elected recent reports of analyses of a variety of lines of Tg mice that sh ow several neuropathological features of AD, including AB-amyloid deposits and dystrophic neurites. Finally, we discuss the several important issues i n future investigations of Tg mice, with particular emphasis on the influen ces of genetic strains on phenotype, especially behavior, and strategies fo r making new models of neurodegenerative disorders. We believe that investi gations of these Tg models will (a) enhance understanding of the relationsh ips between impaired performance on memory tasks and the pathological/bioch emical abnormalities in brain, (b) help to clarify pathogenic mechanisms in vivo, (c) lead to identification of new therapeutic targets, and (d) allow testing of new treatment strategies first in mice and then, if successful, in humans with AD.