The Alzheimer's Disease Tau Platform Clinical Trial
The goal of the Alzheimer's Tau Platform (ATP) is to evaluate the safety and effectiveness of tau-directed therapies, alone or in combination with the anti-amyloid monoclonal antibody, donanemab, in adults aged 50-80 with late preclinical or early prodromal Alzheimer's disease. This platform trial allows for the simultaneous testing of multiple tau therapies under a shared master protocol. This means that multiple investigational products will be tested simultaneously or sequentially. Each investigational product will be tested in a regimen. The main questions the platform trial aims to answer are: * Does a tau-directed therapy, alone or in combination with donanemab, reduce tau buildup in the brain compared to donanemab alone? * Does a tau-directed therapy, alone or in combination with donanemab, slow disease progression based on brain imaging, fluid biomarkers, and measures of memory and thinking? Participants will: * Be randomized to a treatment regimens, each containing different tau therapies. The exact number of treatment regimens that will active at the time of screening will change over time. * Receive donanemab or placebo for 6 months, followed by 24 months of tau therapy alone or in combination with donanemab. * Undergo regular cognitive testing, brain scans (MRI/PET), and biomarker assessments over 30 months Participants will have an equal chance to be randomized to all regimens that are active at the time of screening. Once randomized to a regimen, participants will be randomized to one of three arms: (1) tau therapy alone, (2) a combination of donanemab and tau therapy, or (3) donanemab alone. New regimens will be continuously added as new investigational products become available. The Alzheimer's Tau Platform Trial will enroll additional participants as each new regimen becomes available. ATP will launch with one regimen: Regimen A: AADvac1. In the future, Regimen B (Tau2) will launch with a second tau directed therapy.
• Documentation of the participant's informed consent to study procedures (including APOE genotyping).
• Ages 50-80 years (inclusive). Participants between the ages of 50 and 60 (inclusive) must be mildly impaired at screening (global CDR=0.5 and maximum CDR-SB \<1.5
• Cognitively unimpaired (preclinical AD with a global CDR=0) or mildly impaired (prodromal AD with a global CDR=0.5 and maximum CDR-SB \<1.5).
• MMSE score at screening of 20-30 (inclusive) with educational adjustments:
∙ If \<12 years of education, MMSE required to be \>20.
‣ If 13 to 15 years (inclusive) of education, MMSE required to be \>22.
‣ If \>16 years of education, MMSE required to be \>24.
• Plasma biomarker result at screening that demonstrate the presence of amyloid pathology, consistent with preclinical-prodromal AD.
• Elevated brain tau on PET (MTL or NEO tau SUVr \>1.2) at screening.
• Elevated brain amyloid on PET (centiloids \> 40) at screening.
• Stable doses of permitted medications as described per protocol for a minimum of 30 days prior to screening.
• Resides at home or in the community (assisted living acceptable).
⁃ In the opinion of the site PI, has a study partner able and willing to provide accurate information (including clinical symptoms and medical history) about the participant and participate in study visits and informant-based assessments (usually requires at least 5 hours of contact per week) for the duration of the study.
⁃ As assessed by the site PI, participant is likely to be able to comply with the protocol for the duration of the study, and has adequate vision, hearing (hearing aid permitted), and literacy (English or Spanish) sufficient for compliance with the required testing procedures.
⁃ Must complete all screening evaluations as outlined per protocol.