A number of recent findings support the notion of mechanistic parallels between Alzheimer disease (AD) and oncogenic processes, specifically, that neurons in AD, like cancer cells, display aberrant mitotic cell cycle re-entry. However, the mechanism that drives postmitotic neurons to reenter cell cycle remains elusive. In this study, we focused on the retinoblastoma-related protein p130 in AD. p130 is a transcriptional regulator that complexes with E2F4/5 in the nucleus and suppresses genes that regulate entry into the cell cycle. Interestingly, our results show that there are increases in p130 in cytoplasm of susceptible pyramidal neurons as well as neuroglia, often surrounding senile plaques, and within Hirano bodies in AD. By marked contrast, p130 is found at background levels in non-diseased, age-matched controls. Our data suggest that, despite its upregulation, the aberrant localization of p130 to the neuronal cytoplasm facilitates neuronal cell cycle re-entry in AD.