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 or even in asymptomatic healthy people at risk of AD. Recently FDA announced emergency accelerated approval of mAb Aducanumab for treatment of early AD. However, 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, in this administrative supplement to U01 AG060965, we propose to test the overall safety and immunogenicity of a dual vaccine (DUVAC) targeting Aβ and Tau in non-human primates that more closely resemble the human immune system. These data will support the submission of INDs to the FDA for future clinical trials that will allow us to treat asymptomatic healthy subjects at risk to MCI 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 in non-human primates. Completing studies in aged monkeys along with data from AG060965 safety/toxicology studies in diseased mice should strongly support our IND submission for the first-in-human preventive dual Aβ/tau vaccine with healthy people at risk of MCI or earlier based on research blood, CSF, brain biomarkers.