Amyloid-beta1-42 (Abeta1-42) is crucial to Alzheimer disease (AD) pathogenesis 
but the conformation of the toxic Abeta species remains uncertain. AD risk is 
increased by apolipoprotein E4 (apoE4) and decreased by apoE2 compared with the 
apoE3 isoform, but whether inheritance of apoE4 represents a gain of negative or 
a loss of protective function is also unresolved. Using hippocampal slices from 
apoE knockout (apoE-KO) and human apoE2, E3, and E4 targeted replacement 
(apoE-TR) mice, we found that oligomeric Abeta1-42 inhibited long-term 
potentiation (LTP) with a hierarchy of susceptibility mirroring clinical AD risk 
(apoE4-TR > apoE3-TR = apoE-KO > apoE2-TR), and that comparable doses of 
unaggregated Abeta1-42 did not affect LTP. These data provide a novel link among 
apoE isoform, Abeta1-42, and a functional cellular model of memory. In this 
model, apoE4 confers a gain of negative function synergistic with Abeta1-42, 
apoE2 is protective, and the apoE-Abeta interaction is specific to oligomeric 
Abeta1-42.