Amyloid-β (Aβ) oligomers, found in the brains of Alzheimer's disease (AD) patients and transgenic mouse models of AD, cause synaptotoxicity and memory impairment. Grape seed polyphenolic extract (GSPE) inhibits Aβ oligomerization in vitro and attenuates cognitive impairment and AD-related neuropathology in the brains of transgenic mice. In the current study, GSPE was administered to Tg2576 mice for a period of five months. Treatment significantly decreased brain levels of Aβ*56, a 56-kDa Aβ oligomer previously shown to induce memory dysfunction in rodents, without changing the levels of transgenic amyloid-β protein precursor, monomeric Aβ, or other Aβ oligomers. These results thus provide the first demonstration that a safe and affordable intervention can lower the levels of a memory-impairing Aβ oligomer in vivo and strongly suggest that GSPE should be further tested as a potential prevention and/or therapy for AD.