Expert review recasts ALS, FTD, and LATE as one disease

Clinical takeaway: Most ALS, about half of FTD, and LATE may be forms of a single TDP-43 disease process, a reframing intended to accelerate biomarkers and cross-phenotype trials rather than change diagnosis or treatment today. 

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE) present nothing alike. ALS destroys motor neurons and causes progressive weakness. FTD degrades language, personality, and behavior. LATE is a slow amnestic disorder of the oldest old that mimics Alzheimer disease. Yet all three, along with inclusion body myositis and multisystem proteinopathy, are linked by a pathological signature: transactive response DNA-binding protein 43 kDa (TDP-43) depleted from the nucleus and aggregated in the cytoplasm of neurons, glia, or muscle. More than 2.9 million people in the US have a neurodegenerative disorder marked by that pathology. 

How to define these disorders is a live question across neurology. Alzheimer disease, Huntington disease, and Parkinson-spectrum disease have all moved toward biological definitions in recent years, on the logic that pathology begins before symptoms and that biomarkers and trials work best when anchored to the biology itself. The TDP-43 disorders have not made that transition. Each remains defined by its distinct, inherently late-stage clinical phenotype, even as evidence has accumulated that a common pathobiology runs beneath them. An international consensus review now argues that division has outlived its usefulness. 

The authors propose a new way of grouping these diseases, called TDP-43-associated neurodegenerative disease, or TAND. Under it, most ALS, about half of FTD, LATE, and related conditions are treated as different faces of the same underlying disease. Familiar names like ALS and FTD would stay in use, but as labels for how the disease shows up in a given patient, not as separate diseases in their own right. 

But there is a catch: there is still no reliable way to track TDP-43 pathology across the living nervous system, since confirming it now generally means examining tissue after death. So TAND cannot be diagnosed while someone is alive, and it has no use in the clinic today. They call the missing test an empty box the framework is built to fill. 

Their case for grouping the diseases this way rests on evidence that keeps pointing in the same direction. Harmful variants in more than 20 genes lead to nerve damage with TDP-43 buildup. In healthy cells, TDP-43 sits in the nucleus and blocks a long list of genes from being read incorrectly. The authors argue disease begins when it loses that job and instead clumps up outside the nucleus. The reading errors that follow are distinctive enough that a test could be built to spot them. 

Alongside the new grouping, the review lays out a staging system, running from a positive test with no symptoms at stage 1 to severe disability at stage 6, built along the same lines as the staging now used for Alzheimer and Huntington disease. 

The proposal came out of an informal consensus process that brought together neurologists, neuropathologists, drug developers, biomarker and regulatory experts, patient advocates, and people at high genetic risk, who reviewed the published evidence together. 

The real aim is drug development. A treatment that restores TDP-43's normal function would be expected to help patients no matter which form of the disease they have. That opens the door to trials that enroll people by their biology rather than their diagnosis. It matters because FTD driven by a different protein, tau, would not be expected to respond to a TDP-43 treatment. 

Reaching that point depends on developing a TDP-43-related test. Two are in development: blood or spinal fluid assays that catch the odd protein fragments left when TDP-43 fails, and PET scans that light up the clumped protein in the brain. Their arrival would make the staging system usable. FDA supports defining diseases by their biology, and the authors call their proposal a living document, waiting on broad buy-in from the field. 

"Historically, we've thought about a disease based on its phenotype. But we now think they should be defined by their underlying biology," said Michael Benatar, MD, PhD, the Walter Bradley Chair in ALS Research and executive director of the ALS Center at the University of Miami Miller School of Medicine. "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." 

Source: Benatar M, et al. (2026 Aug 24) JAMA Neurol. TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging