Accumulation of beta-amyloid peptide (Abeta) in the brain is believed to trigger a complex and poorly understood pathologic reaction that results in the development of Alzheimer's disease (AD). Despite intensive study, there is no consensus as to how Abeta accumulation causes neurodegeneration in AD. In this issue of the JCI, Tesseur et al. report that the expression of TGF-beta type II receptor (TbetaRII) by neurons is reduced very early in the course of AD and that reduced TGF-beta signaling increased Abeta deposition and neurodegeneration in a mouse model of AD (see the related article beginning on page 3060). Intriguingly, reduced TGF-beta signaling in neuroblastoma cells resulted in neuritic dystrophy and increased levels of secreted Abeta. Collectively, these data suggest that dysfunction of the TGF-beta/TbetaRII signaling axis in the AD brain may accelerate Abeta deposition and neurodegeneration.