The human apolipoprotein (apo) E4 allele is associated with an early age of onset and increased risk of Alzheimer’s disease (AD). It has been proposed that apoE functions to maintain synaptic integrity in the central nervous system which is supported by studies revealing apoE isoform specific effects in calcium homeostasis, synaptic transmission, and behavior in various animal models. Studies from our lab and two of our collaborators, using a human apoE targeted replacement (TR) mouse model system, provide additional evidence for apoE’s role in synaptic integrity. We previously presented work (SFN 2002 meeting) showing significantly reduced synaptic activity and stunted neuronal morphology in apoE4 compared to apoE3 mice. Our collaboration with Grootendorst et al. shows apoE4 deficits in behavior for spatial and working memory, compared to apoE3. Our collaboration with Trommer et al. demonstrates there is significantly less LTP in apoE4 compared to apoE3 mice. All groups used male human apoE3 and E4 TR mic...