Intraneuronal Aβ-Amyloid Precedes Development of Amyloid Plaques in Down Syndrome

Context.—Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes. Objective.—To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome. Methods.—Histologic and immunocytochemical study of a series of autopsy brains (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 Aβ immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of Aβ) and the formation 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) intracellular accumulation of Aβ in neurons and astrocytes, (2) deposition of extracellular Aβ and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.