The overall objective of this study is to develop an anti-apoE4 therapeutic approach utilizing mAbs that react specifically with apoE4. This will be pursued by experiments directed at the following specific objectives. 1) Inhibition of the in vivo synergistic interactions between apoE4 and the amyloid cascade by anti-apoE4 mAbs. We have recently prepared mAbs that react specifically with apoE4 and have shown in preliminary proof of concept experiments that these mAbs inhibit the apoE4-driven accumulation of brain Aâ following activation of the amyloid cascade. These findings will be extended by assessing the extent to which the apoE4-driven neuronal and cognitive impairments can be blocked by the anti-apoE4 mAbs. This paradigm has the advantage that the anti-apoE4 mAbs are applied into the brain via the Alzet mini pumps together with the neprilisyn inhibitor. 2) Prevention and reversal of the onset of the early brain pathological effects of apoE4 by anti-apoE4 mAbs. We have recently shown that the key hallmarks of AD pathology evolve at a young age. Furthermore, preliminary proof of concept experiments suggest that the tau and Aâ effects of apoE4 in young mice are counteracted by i.p. injection of anti-apoE4. These finding will be presently extended by measurements of the extents to which these apoE4- driven pathological effects and the associated neuronal and cognitive impairments can be either prevented or reversed by i.p. injection of the anti-apoE4 mAbs. Importantly, this model is not biased by a molecular mechanism-driven paradigm, and the results will thus not be confined to a specific molecular theory. 3) Intranasal application of full-length and single-chain anti-apoE4 mAbs. These experiments are directed at developing a non-invasive, clinically compatible, protocol for introducing the anti-apoE4 mAbs into the brain. This will be pursued by intranasal application of the full-length and of smaller single-chain derivatives of these mAbs.