It is widely accepted that Abeta plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) [27]. Attention has been focused mainly on how extracellular Abeta exerts its effects on neuronal cells [7,11,16,32]. However, neuronal degeneration from an accumulation of intracellular Abetax-42 (iAbeta42) occurs in presenilin 1 (PS1) mutant mice without extracellular Abeta deposits [5]. In the present study, intracellular deposits of iAbeta42 are correlated with apoptotic cell death in AD and PS-1 familial AD (PS1 FAD) brains by means of triple staining with antibodies to Abeta, TUNEL, and staining with Hoechst 33342. Neurons simultaneously positive for iAbeta42 and the TUNEL assay were significantly more abundant in AD brains than in controls. The number of apoptotic neurons with intracellular neurofibrillary tangles (iNFTs) was insignificant. Our results indicate that intraneuronal deposition of a neurotoxic form of Abeta seems to be an early event in the neurodegeneration of AD.