Abstract Alzheimer’s disease (AD) is one of the most common in the United States, as the sixth leading cause of death among those 65 or older, and impairing the quality of life for 6.2 million adults as of late 2020. As the population ages, the number of AD patients is expected to grow to over 13.8 million by late 2060 without the development of more effective treatments, straining the capacity of both Medicare and the US caregiving system with the direct costs of AD estimated at $244B and care-giving estimated to reach $305B by 2050. The primary biochemical characteristic of AD is the presence of beta-amyloid (Aβ) plaques and neurofibrillary tangles, primarily composed of hyperphosphorylated tau protein, in the brain. The only FDA approved disease-modifying treatment for AD is Aduhelm, an anti-Ab monoclonal antibody (mAb) that clears Abeta deposits in the AD brain despite not significantly improving cognition. However, its approval has boosted other mAb efforts, including drugs targeting tau tangles, instead of beta amyloid plaques. Aeton has identified ac-tau as a compelling target for mAb treatment of tauopathy in AD and is developing a mAb based treatment. This pathogenic tau modification is highly expressed in the AD brain when compared to healthy controls, The lab of Aeton’s co-founder, Dr. Li Gan, has developed several murine mAbs that strongly bind to the ac-K174 tau protein, effectively reducing taupathy in mouse models. This reduction protected the hippocampus, a region key for memory and learning, from typical AD atrophy, reducing cognitive defects in a mouse model of AD. Aeton has licensed these mAbs for development, humanizing 9 clones to function similarly in human tissue and producing a leading candidate, AT- 01. In this Phase I SBIR application, Aeton has two specific aims: 1) Evaluate the effectiveness of AT-01 in treating in vitro neural cells and organoids in head-to-head comparisons with another anti-tau mAb, HJ8.7, 2) Determine the efficacy and safety of AT-01 against HJ8.7 in a mouse model of tauopathy while evaluating its pharmokinetics and dynamics. At this point, Aeton will evaluate the success of AT-01, determining if it reduces tauopathy by blocking spread and aggregation via targeting the ac-K174 epitope. In a future Phase II application, Aeton would then continue evaluation of AT-01 by initiating IND-enabling studies of efficacy and safety. This Phase I proposal would enable the development of an anti-tau monoclonal antibody treatment for Alzheimer’s disease, with an eye towards clinical translation.