The human APOE4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Long before the onset of AD, cognitive deficits can be identified in APOE4 carriers. It has been proposed that apolipoprotein (apo) E functions to maintain synaptic integrity in the central nervous system during development and during remodeling and repair of neurons. Studies from our lab using a human apoE targeted replacement (TR) mouse model system provide supporting evidence for apoE's role in synaptic integrity. Young (7 month) apoE4 mice show significantly reduced excitatory synaptic activity and dendritic arborization compared to apoES mice, prior to any age-dependent markers of neuropathology. Collaborative studies with the age matched apoE4 mice show deficits in memory and hippocampal LTP compared to apoES mice. We plan to determine when the synaptic deficit begins and which brain regions are vulnerable to APOE4 synaptic deficits. We find significant reductions in specific phospholipid species (i.e. putative essential fatty acids (EFA)) in apoE4 hippocampus compared to apoES mice. These types of fatty acids are required for effective synaptic function. We plan to determine if other brain regions show similar reductions in essential fatty acids. We propose that the observed apoE4 synaptic deficits can be partly explained by alterations in cholesterol and fatty acid metabolism in synaptic membranes. Therefore, we wish to test the following hypotheses. We propose that APOE4 carriers are deficient in maintaining adequate levels of essential fatty acids required for synaptic plasticity, when exposed to an unhealthy diet. That APOE4 synaptic membrane contain a deficit in these EFA which gradually decrease over time under poor dietary conditions. APOE4 synaptic deficits are more prevalent in brain regions containing high plasticity. An inherent deficiency in brain lipid homeostasis exists in APOE4 carriers compared to APOES and APOE2 and that the APOE alleles act in a co-dominant fashion. Completion of our research proposal will provide answers to how APOE4 is linked to increased risk for AD. A unique animal model will be tested for its effectiveness in portraying APOE-dependent decline in synaptic integrity. Novel mechanisms to explain apoE's function in the brain will be elucidated.