Intraneuronal A beta-amyloid precedes development of amyloid plaques in Down syndrome

Context.-Down syndrome patients who live to middle age invariably develop t he neuropathologic features of Alzheimer disease, providing a unique situat ion in which to study the early and sequential development of these changes . Objective.-To study the development of amyloid deposits, senile plaques, as trocytic and microglial reactions, and neurofibrillary tangles in the brain s of young individuals (<30 years of age) with Down syndrome. Methods.-Histologic and immunocytochemical study of a series of autopsy bra ins (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital. Results.-The principal observations included the presence of intraneuronal AP immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of AP) and the f ormation of senile plaques and neurofibrillary tangles. Conclusions.-We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intr acellular accumulation of AP in neurons and astrocytes, (2) deposition of e xtracellular AP and formation of diffuse plaques, and (3) development of ne uritic plaques and neurofibrillary tangles with activation of microglial ce lls.