Trisomy of the whole or distal part of human chromosome 21 (HSA 21) (Ts21) results in Down Syndrome (DS), which is characterized in part by mental retardation and associated neurological abnormalities. Structural abnormalities observed frequently include reduced brain weight, decreased number and depth of sulci in the cerebral cortices, neuronal heterotopias, and reduced numbers of specific populations of neurons, such as granule cells, in the cerebral cortices. Abnormalities in the structure of cells, primarily of the dendrites, are observed in portions of the neuraxis, such as the hippocampus, cerebellum, and cerebral cortices. Functional abnormalities in membrane properties in peripheral structures and in neurotransmitter enzyme systems in both peripheral and central structures are observed also. Brains of DS individuals over the age of 40 exhibit the characteristic neuropathologic and neurochemical stigmata of Alzheimer's disease (AD). The cholinergic and noradrenergic systems appear to be particularly vulnerable. To elucidate the mechanisms responsible for these abnormalities, identification of the genes located in the distal part of HSA 21 and the systematic study of animal model systems with close genetic homology are essential.