Project Summary Immunotherapy is still considered a very promising therapeutic strategy for AD prevention when certain conditions are met. Data from various immunotherapeutic studies support our long- standing tenet that immunogenic AD vaccines could at least delay disease progression when they target both Aβ and Tau pathological molecules at an early stage of the disease before AD manifestation. It is impractical to use very expensive mAbs as a preventive treatment of healthy subjects due to the need for frequent (monthly) administration of high concentrations (700-800mg per IV injection) of this immunotherapeutic. In contrast, almost all effective vaccines are effective when they are used as a preventive treatment. Accordingly, we are seeking a revision to U01 AG060965 that will support a submission of INDs to the FDA for future clinical trials that will allow us to sequentially or concurrently treat early AD subjects with extremely immunogenic Aβ and tau vaccines based on the same and very immunogenic MultiTEP platform and novel adjuvant AdvaxCpG. Our proprietary vaccine platform can stimulate adaptive immunity, providing broad coverage of human MHC polymorphisms and activating both naive Th cells and pre-existing memory Th cells generated in response to conventional vaccines and/or infections with various pathogens during one's lifespan without the activation of harmful autoreactive T cells. These "non-self" Th cells should activate B cells and induce the production of therapeutically potent antibodies specific to pathological Aβ and Tau in humans similar to that we observed in inbred WT and Tg mice as well as outbred rabbits and monkeys. If safe and immunogenic in Phase 1 trials, the AV-1959R/A vaccine could be used as a preventive measure in healthy people at risk of MCI (based on biomarkers) and later used to vaccinate MCI people with the AV-1980R/A vaccine or their combination to delay AD.