The landscape of Alzheimer’s disease (AD) research has reached a historic turning point. With the recent FDA approvals of amyloid-targeting therapies, the scientific community has proven that disease-modifying treatments are possible. However, as any researcher in the field will attest, amyloid is only one piece of a much larger, more complex puzzle. To truly halt the progression of neurodegeneration, we must look deeper into the architecture of the brain—specifically at the tau protein.
The Tau Pipeline Enabling Program (T-PEP), a joint initiative funded by the Alzheimer’s Association and the Rainwater Charitable Foundation (RCF), is the engine driving this next frontier. With the recent opening of its fifth edition (T-PEP V), the program continues its mission to diversify the drug development pipeline.
The Historical Context: Why Tau?
For decades, AD research focused on the amyloid cascade hypothesis, particularly on the beta-amyloid plaques that form outside of neurons. While this led to the first generation of disease-modifying drugs, scientists long observed that the accumulation of tau tangles which form inside the neurons, correlated more closely with cognitive decline and clinical symptoms. Additionally, many forms of neurodegeneration called primary tauopathies have little to no beta-amyloid pathology and are believed to be driven solely by tau.
Tau is a microtubule-associated protein that normally helps stabilize the “tracks” (microtubules) that transport nutrients within brain cells. In AD and more than 20 other neurodegenerative diseases (collectively known as “tauopathies”), tau becomes abnormal, detaches from the microtubules, and forms toxic clumps. These tangles eventually suffocate the neuron, leading to cell death and memory loss.
Despite its clear link to dementia, tau research historically faced a funding gap. It was considered riskier and more difficult to target than beta-amyloid because the protein resides inside the cell. Recognizing this bottleneck, the Alzheimer’s Association partnered with the RCF in 2018 to create T-PEP. The goal was simple but ambitious: to accelerate the transition of tau-related discoveries from the lab to the patient’s bedside.
A Partnership of Impact: RCF and the Alzheimer’s Association
The success of T-PEP is rooted in its unique funding model. The RCF, established by the late billionaire investor Richard Rainwater after his diagnosis of Progressive Supranuclear Palsy (PSP), provides a matching contribution to the Alzheimer’s Association’s funding.
To date, this partnership has awarded over $15 million across 23 grants. By leveraging the Alzheimer’s Association’s global reach and RCF’s deep expertise in tau-specific biology, T-PEP provides the critical resources needed for lead optimization, in vivo proof-of-concept, and IND-enabling studies. These are some of the final, expensive steps required to prove a drug’s safety and efficacy before the FDA allows it to be evaluated in humans.
Retrospective: Successes of Rounds I through IV
The T-PEP program has consistently identified high-potential projects that might otherwise have languished in academic settings due to a lack of translational research funding.
Round I: The Inaugural Class (2018)
The first round set the tone for the program, awarding five grants that explored radically different ways to block or remove tau.
| Principal Investigator | Institution | Program Title |
| Barbara Slusher, Ph.D. | Johns Hopkins University | Regulation of exosome secretion as a novel therapeutic approach for AD |
| Glenn Larsen, Ph.D. | Aquinnah Pharmaceuticals | Therapeutic approach for targeting tau stress granules |
| Jason Gestwicki, Ph.D. | University of California, San Francisco | High content screen for new targets that reduce free tau |
| Karen Ashe, M.D., Ph.D. | University of Minnesota | Targeting caspase-2 to repair synaptic transmission in tauopathy |
| Marc Diamond, M.D. | University of Texas Southwestern Medical Center | Small molecules to block tau pathology |
Round II: Diversifying the Portfolio (2020)
As the program matured, T-PEP II awarded additional groups, expanding the search to include international researchers for the first time.
| Principal Investigator | Institution | Program Title |
| Albert La Spada, M.D., Ph.D. | University of California, Irvine | Evaluation of PPAR-delta agonist therapy as a treatment for tauopathy |
| Daniel Chain, Ph.D. | TauC3 Biologics | TauC3: a key tauopathy culprit and an antibody to mitigate its effects |
| Janice Kranz, Ph.D. | Eikonizo Therapeutics | HDAC6 inhibitors to treat tauopathies: proof of mechanism |
| Jeff Friedman, M.D., Ph.D. | DTx Pharma | Safe and effective delivery of MSUT2 siRNA for treatment of tauopathy |
| Kenneth Kosik, M.D. | University of California, Santa Barbara | Farnesyl transferase inhibitors to treat tauopathies |
| Matthew Disney, Ph.D. | Scripps Research Institute | Reducing tau burden by targeting its RNA with small molecules |
| Patrik Verstreken, Ph.D. | Flanders Institute for Biotechnology VIB | Therapeutic strategies to target tau-synaptogyrin-3 interaction |
| Stephen J. Haggarty, Ph.D. | Massachusetts General Hospital | Bifunctional tau degraders as a novel therapeutic strategy for tauopathy |
Round III: Refining the Pipeline (2022)
In the third round, T-PEP awarded its first repeated recipient (Aquinnah Pharmaceuticals), demonstrating the positive impact of a T-PEP grant on advancing a program. Overall, the funded programs shifted toward advanced preclinical stages and novel targeting mechanisms, including:
| Principal Investigator | Institution | Program Title |
| Glenn Larsen, Ph.D. | Aquinnah Pharmaceuticals | Targeting tau stress granules for the treatment of tauopathies |
| Gregory Petsko, D.Phil. | Brigham and Women’s Hospital | Enhancing retromer function: a novel therapeutic strategy for tauopathies |
| Luc Buée, Ph.D. | University of Lille, Inserm | Nanotau |
| Paul Fraser, Ph.D. | University of Toronto | SUMO2 protein replacement therapy to counteract tau toxicity in AD |
| Peter Sazani, Ph.D. | AcuraStem Inc. | Late-stage development of a PIKFYVE antisense oligonucleotide treatment for tauopathy |
Round IV: Emphasis on Advancement (2024)
The fourth round of T-PEP was awarded to a promising group of programs that were primarily international and included emerging therapeutic approaches to address tau pathology.
| Principal Investigator | Institution | Program Title |
| Antje Willuweit, Ph.D. | Priavoid GmbH | Optimization of lead compounds for the disassembly of toxic tau aggregates |
| Fleur Ferguson, Ph.D. | University of California, San Diego | Phosphoediting as a therapeutic strategy in tauopathies |
| Frank Longo, M.D., Ph.D. | Stanford University | Neurotrophin receptor ligands to treat tau-associated synaptic degeneration |
| John Skidmore, D.Phil. | University of Cambridge – Alborada Drug Discovery Institute | Clinical candidate gene therapy to enhance tau proteasomal clearance |
| Timo Myöhänen, Ph.D. | University of Helsinki, Polku Therapeutics | Novel PREP ligands as a disease-modifying therapy for tauopathies |
The Milestone: T-PEP V and the Future
T-PEP bridges the gap between a brilliant idea in the lab and a life-changing treatment in the clinic. Because of the joint commitment of the RCF and the Alzheimer’s Association, we are closer than ever to a world where tauopathy can be a treatable condition.
The opening of the fifth edition of T-PEP marks a significant milestone. It signals that the tau therapeutic pipeline is a robust, active ecosystem of potential therapies, and marks a continued investment in the years ahead. To truly win the fight against AD and other tauopathies like PSP, we likely need a tau-targeted therapy approach. The projects funded today aim to be the clinical trials of tomorrow, and ultimately, the therapies that could save millions of families and loved ones from the burden of dementia.
For more information on the Tau Pipeline Enabling Program and how to apply for the fifth edition, visit alz.org/t-pep. You may also reach out to the RCF medical research staff at medgrants@rainwatercf.org.
