DESCRIPTION (provided by applicant): The broad long-term objective of this proposal is to understand how memory loss occurs in Alzheimer's disease (AD). We have recently shown that a specific amyloid beta (AP) assembly that we named A¿*56was likely the cause of cognitive decline in the mouse model of AD, Tg2576. The immediate objective of our research is to confirm the existence of A¿*56 in the human brain. We will also evaluate the presence of A¿*56 relative to the cognition status of the three groups (normal, MCI and AD) present in our cohort in order to support our hypothesis that A¿*56disrupts memory function in the brain. In a longer term, we propose to decipher the mechanism of action of A¿*56in Tg2576 mice combining in vitro and in vivo paradigms. Finally we plan to evaluate whether A¿*56represent the A(entity connecting the two phenotypic hallmarks of the disease, namely amyloid plaques and neurofibrillary tangles. If completed this proposal could provide novel approaches for treating Alzheimer's disease because its objective is focusing on identifying what causes memory loss and how memory loss occurs in early or pre- Alzheimer's disease, stage at which the integrity of the brain is still intact.