Amyloid-beta peptide (Abeta) oligomers are likely to underlie the earliest amnesic changes in Alzheimer's disease through impairment of synaptic function. A recent work from the laboratories of Tae-Wan Kim and Gilbert Di Paolo and colleagues implicates the phosphoinositide signaling pathway in synaptic changes due to elevation of Abeta oligomers. Given that phosphatidylinositol 4,5-bisphosphate (PIP2) is central to many essential processes in neurons including neuronal and synaptic function, reduction in the levels of PIP2 in response to oligomeric Abeta could explain many of the phenotypes that have been observed with oligomeric Abeta. The data open up a new target for protecting neurons from Abeta-induced synaptic impairment.