Insight the Future of Anti-Tau Drug Development for Alzheimer Disease

November marks Alzheimer Awareness Month, a time when the field places added focus on early detection, therapeutic innovation, and the realities of living with a disease that continues to affect millions worldwide. While recent progress in amyloid-directed monoclonal antibodies has generated new momentum, researchers and clinicians have increasingly turned their attention to tau pathology, which correlates more closely with symptom severity and disease progression. Tau’s central role in neuronal injury, along with advances in tau PET imaging and plasma biomarkers such as p-tau181 and p-tau217, has positioned tau-targeted therapeutics as one of the most closely watched areas in Alzheimer research.

Against this backdrop, Charles Bernick, MD, staff neurologist at the Cleveland Clinic Lou Ruvo Center for Brain Health, provided insight into the evolving scientific and clinical rationale for anti-tau therapies. His work during Alzheimer Awareness Month reflects the broader shift in the field toward preventing tau aggregation, halting trans-synaptic tau spread, and improving precision in patient selection using emerging biomarker tools. In this Q&A, Bernick discussed the mechanistic distinctions between amyloid and tau targets, highlights leading therapeutic strategies in development, and identifies key unanswered questions that will shape future trial design and clinical implementation.

NeurologyLive: Can you describe the rationale behind targeting tau pathology in Alzheimer disease, and how it differs mechanistically from amyloid-directed therapies?

Charles Bernick, MD: The pathological hallmark of Alzheimer's disease (AD) is the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles made up of phosphorylated tau (ptau) protein.

Amyloid plaque accumulation is one of the earliest pathological features of AD yet is not associated with severity of symptoms. On the other hand, ptau has the ability to spread from cell to cell and is linked to worsening symptoms and disease progression.

It's presumed early role in the disease process, along with its' extracellular location, made amyloid an appealing target of treatment. Among the various approaches to anti-amyloid therapy, the most successful have been monoclonal antibodies that have demonstrated the ability to remove amyloid plaques and slow disease progression. However, a major gap in AD therapeutics has been the inability to arrest ptau seeding and spread. Challenges to utilizing anti-tau strategies is dealing with the intracellular location of tau and somehow interfering with its' cell-to-cell seeding process.

How do tau aggregates correlate with disease progression and clinical symptoms compared with amyloid burden?

Though amyloid deposition is one of the earliest biomarker features that can be identified in Alzheimer's disease (AD), progressive phosphorylated tau deposition is best associated with symptom severity and disease progression. On the other hand, amyloid burden does not necessarily predict clinical symptoms.

What are the most promising anti-tau approaches currently in development—such as monoclonal antibodies, antisense oligonucleotides, or small-molecule inhibitors—and how do their mechanisms differ?

There are currently a variety of potential mechanisms to interfere with tau accumulation and spread which include:

Tau immunotherapies - it has been shown that anti-tau antibodies can enter neurons and bind to tau, along with inhibiting tau propagation between neurons in culture. Both active (vaccine) and passive ( monoclonal antibodies) immunological agents are the group most studied so far with several agents in testing presently.

Antisense oligonucleotides - these agents target MAPT mRNA to reduce the expression of tau.

Small molecule inhibitors- A number of other approaches have been proposed to reduce tau burden including drugs that can prevent tau aggregation, stabilize micortubules, or alter tau protein modifications that occur in AD.

How are PET imaging and fluid biomarkers (like p-tau218 or p-tau181) shaping clinical trial design and patient selection?

Our ability to identify individuals with AD pathology through PET amyloid imaging and emerging plasma biomarkers with high accuracy and in preclinical stages has revolutionized conduct of AD trials. The most obvious benefit is disease ascertainment - knowing those in the trial actually have the disease we want to treat. In addition, plasma biomarkers provide the ability to more efficiently screen potential trial participants; this has tremendous value in recruiting for preclinical AD trials, where participants are asymptomatic and there is likely going to be a high screen fail rate. In addition, the biomarkers play an important role in assessing the study drug's target engagement, as well as functioning as outcome measures in early phase trials.

What are the biggest unanswered questions in tau-directed therapy research—are we targeting the right tau species, epitopes, or disease stage?

All of the above! Of the many unanswered questions for immunotherapies is what is the best tau epitope or species to target. Should these drugs be used as first line therapies, in combination with anti-amyloid agents, or sequentially following amyloid plaque removal? With anti-amyloid medications being standard of care for individuals with mild AD, how do we factor that in design of trials? Can we design tau trials that can be more easily translated to the clinic? However, given the promise of anti-tau strategies, there is additional hope in the field of more effectively halting AD disease progression.