Research and Innovation
TAND: A New Framework for ALS, FTD and Related Brain Diseases
By: Josh Baxt | August 24, 2026 | 10 min. read |
A major international review led by University of Miami Miller School of Medicine neurologist Dr. Michael Benatar argues that some diseases, including ALS, frontotemporal dementia and LATE, should be classified by their shared TDP-43 biology
On the surface, amyotrophic lateral sclerosis (ALS),frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) might seem like unrelated diseases. ALS destroys motor neurons, causing muscle weakness and paralysis. FTD hits the brain’s frontal and temporal lobes, affecting language, personality and behavior. LATE is a slowly progressing memory disorder that resembles Alzheimer’s disease and tends to affect people older than 85
But for all these distinctions, ALS, FTD and LATE share an important biological foundation, a protein called TDP-43. This commonality is generating an important question. Should we place greater emphasis on a disease’s biological underpinnings than we do on its symptoms and other traits (phenotypes)?
To help answer this question, a large international group of clinicians, researchers and others, led by Michael Benatar, M.D., Ph.D., the Walter Bradly Chair in ALS Research, chief of the Neuromuscular Division, professor of neurology and executive director of the ALS Center at the UHealth—University of Miami Health System and the University of Miami Miller School of Medicine, have authored a paradigm-shifting review
Why This Research Matters
A new international review proposes grouping diseases according to the biology driving them. Researchers call this framework TDP-43 Associated Neurodegenerative Disease (TAND)
- Accelerate treatment development: Therapies targeting TDP-43 could potentially be used across multiple diseases that share the same underlying pathology.
- Improve clinical trials: Better identification of patients with TDP-43 pathology could help researchers test treatments in the people most likely to benefit.
- Enable earlier detection: Biomarkers tied to TDP-43 may eventually help identify disease before symptoms become apparent.
- Support rare disease research: A shared biological framework could expand therapeutic opportunities for patients with uncommon neurodegenerative disorders.
Ultimately, the TAND framework aims to shift the conversation from what symptoms a patient has to what biology is causing the disease, a change that could reshape how neurodegenerative diseases are studied, diagnosed and treated
Published in JAMA Neurology, the paper dives into TDP-43’s relationship with ALS, FTD, LATE and other severe neurodegenerative conditions. The research team coined the term TDP-43 associated neurodegenerative disease (TAND) to describe these relationships. Viewing these diseases through a biological lens could profoundly impact biomarker research, clinical trials and eventually clinical care
“Historically, we’ve thought about a disease based on its phenotype,” said Dr. Benatar. “But we now think they should be defined by their underlying biology. The phenotypes are simply manifestations of that disease biology. We don’t want to do away with clinically useful terms, such as ALS and FTD, but we need to see them for what they are.”
The Critical Role of TDP-43 in RNA Splicing
While TDP-43 may have several functions, its main role is regulating a ubiquitous biological mechanism called RNA splicing. When a gene expresses RNA (which is eventually translated into a protein), that RNA can be put together (spliced) in different ways. This allows one gene to make similar but distinct forms of the same protein
TDP-43 helps oversee this process to prevent mistakes. Unfortunately, in ALS, LATE and around half of FTD cases, TDP-43 cannot perform this task, leading to aberrant RNA splicing. As a result, cells generate abnormal forms and quantities of proteins. This central role in splice regulation may explain why TDP-43 is relevant to so many neurodegenerative conditions
“Hundreds of genes rely on TDP-43 for proper splicing,” said Sami Barmada, M.D., Ph.D., the Angela Dobson Welch and Lyndon Welch Research Professor at the University of Michigan and a co-author on the review. “To do this job, TDP-43 must be in the nucleus, but in disease, TDP-43 instead builds up in the cell’s cytoplasm. It is this combination of TDP-43’s absence from the nucleus and its accumulation in the cytoplasm (TDP pathology) that may be critical for disease.”
Why TAND Could Change Drug Development
TAND is a different way to think about neurodegenerative conditions, but it’s far more than a philosophical construct. This common link between ALS, FTD, LATE and other diseases could profoundly impact drug development
“If somebody has ALS with TDP-43 pathology, and another person has FTD with TDP-43 pathology, the same treatment will likely work in both people,” said Corey McMillan, Ph.D., associate professor of neurology at the University of Pennsylvania and co-author on the review. “It makes no sense to develop separate TDP-43-targeting therapies for each disease.”
Frequently Asked Questions
What is TAND?
TDP-43 Associated Neurodegenerative Disease (TAND) is a proposed framework that groups conditions such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) according to their shared TDP-43 biology rather than their symptoms. Researchers believe this approach could improve diagnosis, biomarker development and treatment discovery
What is TDP-43?
TDP-43 is a protein that helps regulate RNA splicing, a process cells use to assemble genetic instructions before making proteins. When TDP-43 becomes dysfunctional, cells can produce abnormal proteins or fail to produce important proteins altogether
How are ALS and frontotemporal dementia connected?
Although ALS primarily affects movement and FTD affects behavior, language and cognition, many cases of both diseases share TDP-43 pathology. This common biology suggests they may be different manifestations of related underlying disease processes
Why are researchers proposing a new disease framework?
Researchers argue that neurodegenerative diseases should be classified not only by symptoms but also by the biological mechanisms driving them. A biology-first approach may provide a clearer path for research and therapeutic development
Could TAND lead to new treatments?
Potentially. If multiple diseases share TDP-43 pathology, therapies that target TDP-43 could be developed for several conditions rather than for each disease separately. This could accelerate drug development and expand treatment options, particularly for rare disorders
Could TDP-43 help detect disease earlier?
Researchers suggest that monitoring TDP-43-related changes may eventually help identify neurodegenerative disease before symptoms appear, creating opportunities for earlier intervention and prevention strategies
“This is an especially important insight for ultra-rare forms of disease that are associated with TDP-43 pathology,” explained Edward Lee, M.D., Ph.D., John Q. Trojanowski, M.D., Ph.D. Professor for Neurodegenerative Disease Research at the University of Pennsylvania and review co-author
Earlier Detection and Smarter Clinical Trials
The research team’s work could also impact clinical trials. FTD patients can have two distinct pathologies, one based on TDP-43 dysfunction and another driven by tau protein accumulation. While FTD-TDP-43 patients would likely respond to a TDP-43-focused treatment, FTD-tau patients would not respond at all
This underscores the importance of understanding the biology of each person’s disease to effectively populate clinical trials, but there’s another layer. Monitoring TDP-43 could potentially help clinicians recognize ALS, FTD and other conditions long before symptoms appear, which will be essential for disease prevention
A Living Document
This review will almost certainly be part of an ongoing conversation. Researchers continue to learn more about TDP-43 and how it becomes dysfunctional. For example, since TDP-43 pathology affects the splicing of many different proteins, current studies are focusing on potentially important upstream mechanisms that could influence TDP-43 activity
In the larger picture, the authors hope this framework will inspire more creative approaches to recognize, treat and ultimately prevent neurodegenerative diseases
“We need broad buy-in from the community to incorporate TAND into our thinking,” said Dr. Benatar. “When we wrote this, we purposefully brought in clinicians who specialize in ALS, FTD, and LATE, as well as patient advocates and representatives from biotechnology groups and the pharmaceutical industry. If we’re going to change how the field thinks about these conditions, we need everyone involved.”
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Tags:Aging Research, ALS, Alzheimer’s disease, amyotrophic lateral sclerosis, cognitive decline, Dr. Michael Benatar, Frontotemporal dementia, memory disorders, Newsroom
