Aβ accumulates in the AD brain as amyloid within senile plaques and other smaller, soluble aggregates (oligomers). Aβ plaques are associated with a chronic inflammatory state, including reactive astro- and microgliosis and increased production of numerous inflammatory proteins. Chronic inflammation is hypothesized to induce a complex set of changes in neurons that may ultimately lead to neurodegeneration. The neuroprotective cytokine TGF-β is increased in AD and may reduce deposition of Aβ as plaques while enhancing deposition in the cerebral vessels. In this issue of the JCI, Tesseur et al. (8) show that there is reduced TGF-β signaling in the AD brain, which in turn may promote neuronal degeneration by suppression of neurotrophic factor expression or dysfunction of other unknown neuroprotective pathways. Decreased TGF-β signaling in neurons may also increase Aβ levels, enhancing amyloid deposition. Thus, the inflammatory response to Aβ deposits may initiate a positive feedback loop that exacerbates, rather than ameliorates, AD pathology.