APOE genotype is by orders of magnitude the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The ?4 allele increases risk of AD by ~ 3.7 fold and 2 copies ~ 12 fold; the ?2 allele decreases risk by ~ 50%. Evidence strongly suggests that a major reason underlying these effects is related to the ability of the apoE protein to interact with the amyloid- (A) peptide and in an isoform-dependent fashion influence A clearance and aggregation. ApoE may also influence brain function and dysfunction via additional mechanisms such as influencing synaptic/network activity and lipid metabolism. It is not yet clear how to target apoE biology to develop therapeutic strategies. Our preliminary data suggest the hypothesis that apoE4, when present in the brain interstitial fluid (ISF), reduces A clearance and enhances A oligomerization/fibrillization, as well as synaptic damage. Increasing apoE2, E3, and E4 via gene delivery methods decreases, is neutral, or increases A aggregation and its associated toxicity. Decreasing the amount of toxic apoE/A complexes might serve as a therapeutic approach. In fact, our preliminary data utilizing monoclonal antibodies to apoE shows strong effects of decreasing A pathology and improving brain network function possibly via microglial-mediated clearance of A aggregates. We hypothesize that 1) decreasing A aggregation and toxicity may be possible by increasing apoE2 levels in the ISF of the brain; 2) targeting apoE/A aggregates with anti-apoE antibodies may serve as a potential therapeutic approach; and 3) that apoE in the ISF and at the synapse may play important non-A related functions, which will be critical to understand in the context of any therapeutics based on an apoE mechanism. The specific aims are: 1) To determine whether altering apoE isoform level in specific compartments in the brain influences A pathology and associated A-dependent brain dysfunction in an isoform-specific and A-dependent manner. 2) To explore the effects of anti-apoE antibodies and their mechanism of action in human APP transgenic (Tg) mice expressing human apoE isoforms. 3) To explore potential effects of apoE isoforms on synaptic structure/network function in human apoE knockin mice, wild-type, and apoE knockout mice +/- A.