Alois Alzheimer in 1907. Despite considerable progress APP has not been established. in elucidating the molecular components of the brain The biological functions of APP in vivo have recently lesions, the mechanism of neuronal degeneration in AD been examined in homozygous APP-knockout mice. hasbeen unclear. However, recent advancesin molecu-APP-knockout mice proceed through gestation norlar genetics have focused attention on several pathomally, suggesting that APP is not absolutely required genic mechanisms. There are now four different genes during development (Zheng et al., 1995). As adults, they that confer susceptibility to AD—the amyloid precursor exhibit a 15%–20% decrease in weight, decreased locoprotein (APP), apolipoprotein E (ApoE), and two novel motor activity, and forelimb motor abnormalities. The seven transmembrane domain proteins. Although it is only detectable abnormality in the brain is diffuse reaclikely that multiple molecular pathways can lead to AD, tive gliosis without clear evidence of neuronal degeneraa central issue is whether all causes of the disease lead tion. The minimal cortical pathology in the complete to a final common mechanism of neuronal death. This absence of APP is somewhat surprising in light of the review describes recent advances in the molecular ge- known effects of APPs on neurons in vitro, raising the netics and cell biology of AD and discusses the potential possibility that the APP deficit may have been partially pathogenic mechanisms that emerge. compensated. Another mouse model has been developed in which a mutant form of APP lacking exon 2 is expressed. These animals exhibit cognitive impairment