PROJECT SUMMARY The DIAN-TU platform was formed to design and manage interventional therapeutic trials and find a treatment that provides cognitive benefit for those certain to develop dominantly inherited AD (DIAD). The DIAN-TU trial platform is now fully operational in 13 countries and 37 sites. The current DIAN-TU secondary prevention trial is a four-year phase 3 cognitive endpoint trial of two anti-amyloid drugs, solanezumab and gantenerumab, with results to be announced in early 2020. The DIAN-TU platform is now mature and primed for testing treatments targeting tau or a combination of tau and amyloid-beta (Aβ) depending on the outcomes of the amyloid trials, and is the ideal platform to provide pivotal biologic results of tau treatment in a pure form of AD. If there is a positive outcome of Aβ drugs, this would support all subjects to be on therapy, enabling combination treatment and giving tau drugs a greater chance of success. If Aβ drugs are negative, then we will need to address the ability of tau-targeted drugs to impact the biology of AD and the potential to slow or prevent the disease. Thus, the tau NexGen studies can and should be done regardless of the outcomes of current amyloid trials. The next phase of the DIAN-TU Next Generation (NexGen) trial will test diverse tau targets in the DIAD population using three mechanisms: a tau antibody, a genetic treatment, and an aggregation inhibitor. The DIAN-TU Tau NexGen will conduct randomized, double blind, pooled placebo-controlled, two-year phase 2 biomarker endpoint trials of three anti-tau or anti-tau/anti-Aβ combination therapies in 216 DIAD mutation carriers (MCs, 72 in each drug arm) who are mildly symptomatic (CDR 0.5 or 1) or asymptomatic with an estimated year of symptom onset (EYO) 15 years before to 10 years after EYO. The trial platform has five novel trial design aspects: 1) a dose escalation algorithm to safely maximize target engagement; 2) a common-close design, so all subjects will stop treatment when the last enrolled subject completes the two- year treatment; 3) a pooled placebo/control design, which increases the number of subjects who contribute to the primary analysis; 4) novel imaging (e.g., the latest generation tau PET tracer, diffusion basis spectrum imaging MRI) and biofluid measures of soluble tau species, neurodegeneration, and inflammation; and 5) a cognitive and tau PET run-in period. The DIAN-TU's contribution is expected to be a substantial understanding of the key tau and combination therapeutic targets in AD through the use of an innovative trial platform in an ideal population. This contribution would provide the AD field with a greater likelihood of translating promising anti-tau therapies to large phase 3 studies, accelerating disease-modifying therapies in DIAD, and possibly translating to the more common sporadic form of AD. Our future aims are to transition successful phase 2 biomarker outcome studies to phase 3 cognitive endpoint outcome studie...