Alzheimer's disease (AD) brains display A beta (Aβ) plaques, inflammatory changes and neurofibrillary tangles (NFTs). Converging evidence suggests a neuronal origin of Aβ. We performed a temporal study of intraneuronal Aβ accumulation in Down syndrome (DS) brains. Sections from temporal cortex of 70 DS cases aged 3 to 73 years were examined immunohistochemically for immunoreactivity (IR) for the Aβ N-terminal, the Aβ40 C-terminus and the Aβ42 C-terminus. N-terminal antibodies did not detect intracellular Aβ Aβ40 antibodies did not detect significant intracellular Aβ, but older cases showed Aβ40 IR in mature plaques. in contrast, Aβ42 antibodies revealed clear-cut intraneuronal IR. All Aβ42 antibodies tested showed strong intraneuronal Aβ42 IR in very young DS patients, especially in the youngest cases studied (e.g., 3 or 4 yr. old), but this IR declined as extracellular Applaques gradually accumulated and matured. No inflammatory changes were associated with intraneuronal Aβ. We also studied the temporal development of gliosis and NFT formation, revealing that in DS temporal cortex, inflammation and NFT follow A β deposition. We conclude that Aβ42 accumulates intracellulary prior to extracellular Aβ deposition in Down syndrome, and that subsequent maturation of extracellular Aβ deposits elicits inflammatory responses and precedes NFTs.