Amyotrophic Lateral Sclerosis & Frontotemporal Dementia
Amyotrophic lateral sclerosis, or ALS, is a progressive disease in which Betz cells in the brain and alpha-motor neurons in the spinal cord gradually stop working and die. These are crucial for control of voluntary motion. Frontotemporal dementia, or FTD, is a group of disorders that primarily damage the frontal and temporal lobes of the brain, leading to changes in behavior, personality, language, and judgment. Although they can look very different at first, ALS and FTD are now understood to sit on a disease spectrum rather than being completely separate conditions. This is because, while symptoms are generally very different, the underlying biology, genetics, and pathology have significant overlap. Some people with ALS develop cognitive or behavioral symptoms, some people with FTD develop motor neuron disease, and some have a mixed ALS-FTD presentation from the start.
ALS most often affects adults in mid to late life, while FTD often begins earlier than Alzheimer’s disease, frequently between ages 45 and 65. That earlier onset is one reason FTD can be especially disruptive: it often affects people during their working years and family life. A defining feature across much of the ALS/FTD spectrum is that the disease does not only damage one “spot” in the nervous system. Instead, it affects vulnerable networks, including motor circuits, language networks, and brain systems involved in behavior and executive function.
Pathology
The central biological hallmark in most ALS cases and in about half of FTD cases is abnormal TDP-43 localization. TDP-43 is a protein that normally resides in the nucleus of the cell, where it helps regulate how RNA is processed. In disease, it is often absent from the nucleus and accumulates abnormally in the cytoplasm, where it forms aggregates. This is important not only because the protein clumps are present, but because the cell also loses TDP-43’s normal function.
That loss of normal TDP-43 function has major downstream effects. It disrupts RNA processing and splicing, which means neurons can start making the wrong versions of important molecules or fail to make enough of the right ones. Two especially important downstream targets that have received a lot of attention are STMN2 and UNC13A, both of which are involved in neuronal maintenance and function. When TDP-43 is in the cytosol, instead of in the nucleus, these proteins are made incorrectly due to a process called cryptic exon inclusion, leading to less or dysfunctional protein. This helps explain why TDP-43 pathology is increasingly viewed not just as a marker of disease, but as a driver of it.
Other pathological features depend on the subtype. In ALS, there is degeneration of upper and lower motor neurons, leading to muscle weakness, twitching, spasticity, and eventual paralysis. In FTD, there is progressive degeneration of neurons in the frontal and temporal lobes, which can produce apathy, disinhibition, compulsive behaviors, loss of empathy, or language impairment. In inherited forms, other proteins may be involved too, including tau or FUS in some FTD subtypes and SOD1 in a subset of ALS cases.
Biological Pathways
One of the main pathways involved in ALS/FTD is RNA dysregulation. Neurons rely heavily on precise RNA processing to maintain long, complex cellular architecture and rapid communication. When proteins such as TDP-43 fail, many downstream RNA programs begin to break down. This can alter synaptic function, axonal maintenance, stress responses, and the cell’s ability to adapt to injury because the proteins involved in these pathways are not being made correctly.
A second major pathway is proteostasis failure, meaning the cell can no longer properly fold, traffic, and clear proteins. Damaged or mislocalized proteins accumulate, while systems such as the proteasome and autophagy-lysosome pathway become less able to keep up. Over time, this creates a toxic environment in which neurons are forced to function under chronic stress.
Axonal degeneration is also a critical part of the disease, especially in ALS and ALS-FTD. Motor neurons are unusual cells because their axons can extend extraordinary distances from the spinal cord to the muscles. That makes them especially vulnerable when their maintenance systems begin to fail. One of the most important discoveries in this area came from the work of Jeffrey Milbrandt, Aaron DiAntonio, and colleagues, who helped establish SARM1 as a central executioner of programmed axon degeneration. When activated, SARM1 rapidly depletes NAD+, a molecule essential for cellular energy balance, and this helps trigger axon self-destruction. That pathway has become a major therapeutic target because it may be possible to interrupt axon loss even when upstream stress is still present.
Neuroinflammation, mitochondrial dysfunction, impaired nucleocytoplasmic transport, and altered stress granule biology also contribute to the disease process. These pathways do not act in isolation. They interact and reinforce one another, which is one reason ALS/FTD is so difficult to treat with a single one-size-fits-all approach.
Causes
Most ALS and FTD cases are sporadic, meaning they are not caused by a single clear trigger. But in a substantial minority genetics plays a major role, especially in familial disease. The most important shared genetic cause across ALS and FTD is an expanded repeat in the C9orf72 gene. This discovery was a turning point because it helped solidify the idea that ALS and FTD are deeply linked diseases with overlapping biology.
Other genes associated with the ALS/FTD spectrum include TARDBP, FUS, SOD1, TBK1, OPTN, VCP, and GRN, among others. These genes point toward several recurring disease themes: RNA regulation, protein quality control, and vesicle trafficking. In other words, even when the exact mutated gene differs, the vulnerable systems are often similar.
Environmental and lifestyle factors are much less clearly defined than the genetic contributors. For most sporadic cases, the disease likely emerges from a combination of age-related vulnerability, cellular stress, and individual genetic background. Age remains a major risk factor, but unlike Alzheimer’s disease, FTD often appears at a younger age.
Progression
ALS usually begins with focal weakness, such as difficulty with hand function, tripping, slurred speech, or trouble swallowing, and then spreads to other muscle groups over time. As more motor neurons are lost, muscles weaken and waste away. Eventually, many people develop severe disability related to mobility, communication, swallowing, and breathing. The pace of progression varies widely, but ALS generally progresses more rapidly than many other neurodegenerative diseases.
FTD progression depends on the subtype. In behavioral variant FTD, early changes often involve personality, judgment, motivation, and social behavior. In primary progressive aphasia, language becomes the most affected domain, with either word-finding problems or loss of word meaning depending on the subtype. Over time, symptoms broaden, daily independence declines, and some patients develop overlap with motor neuron disease or parkinsonian features.
In the mixed ALS-FTD form, physical and cognitive symptoms can reinforce one another in especially challenging ways. This overlap is important clinically because it affects decision-making, caregiver burden, safety, and the kinds of support a patient may need over time.
Treatment Landscape
Current treatment for ALS remains only partially effective, but the landscape is broader than it used to be. Existing therapies aim to modestly slow progression, manage symptoms, support breathing and nutrition, and preserve quality of life for as long as possible. Multidisciplinary care, including neurology, respiratory care, physical therapy, speech therapy, mobility support, and nutrition, is a major part of treatment because supportive care has a meaningful impact on both function and survival.
For FTD, there is still no approved disease-modifying therapy, so management focuses on symptoms, safety, routines, caregiver education, and treatment of related behavioral or mood issues when appropriate. This makes the need for better biologically targeted therapies especially urgent.
One of the more exciting future directions, especially for ALS and possibly ALS-FTD with prominent axonal degeneration, is targeting SARM1. The Milbrandt and DiAntonio labs were central to defining SARM1 as a key executioner of axon degeneration, and that work helped create the rationale for an entirely new therapeutic strategy: blocking the self-destruction program inside injured or stressed axons. Disarm Therapeutics, now owned by Eli Lilly, is developing SARM1 inhibitors, and Lilly announced in 2025 that its oral SARM1 inhibitor LY3873862 was entering the Healey ALS Platform Trial. That does not yet mean the strategy will work in patients, but it is one of the clearest examples of a mechanistically grounded axon-protection approach moving toward clinical testing.
The broader treatment pipeline also includes antisense therapies for specific genetic forms of disease, efforts to restore TDP-43-related biology, and approaches aimed at neuroinflammation, proteostasis, and synaptic or axonal maintenance. The field is increasingly shifting from symptom control alone toward targeted disease modification.
Research Directions
One major research direction is better understanding TDP-43 biology. Because TDP-43 pathology sits at the center of so much of the ALS/FTD spectrum, researchers are trying to measure it earlier, track it more precisely, and intervene before irreversible degeneration has occurred. Biomarker development is a large part of this effort, including fluid markers that may reflect TDP-43 dysfunction before full clinical decline.
Another major goal is precision medicine. For genetically defined disease, such as with mutations in C9orf72 or SOD1, there is increasing interest in tailoring treatment to the underlying mutation. Even in sporadic disease, scientists are trying to divide patients into more biologically meaningful subgroups rather than treating ALS or FTD as a single uniform disorder.
Axon protection is also becoming a more prominent theme. The reason is straightforward: even if scientists cannot immediately fix every upstream defect, preserving axons and synapses could still slow the loss of function that matters most to patients. That is part of why the SARM1 pathway has generated so much interest. More broadly, the field is moving toward combination thinking, where future treatment may need to protect axons, reduce toxic protein dysfunction, and support stressed neurons all at once.
Sources
- Neumann et al. “Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis.” Science. 2006.
- Shuo-Chien Ling, Magdalini Polymenidou, and Don W. Cleveland. “Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis.” Neuron. 2013.
- Robert H. Brown Jr. and Ammar Al-Chalabi. “Amyotrophic Lateral Sclerosis.” New England Journal of Medicine. 2017.
- DeJesus-Hernandez et al. “Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS.” Neuron. 2011.
Molecular Genetics
Genetic Profiles & Variants
Understanding the genomic landscape of neurodegeneration, from hereditary mutations to complex sporadic risk factors.
The most frequent genetic cause of ALS and FTD, characterized by pathogenic hexanucleotide repeat expansions in the first intron, leading to RNA toxicity and dipeptide repeat protein aggregation.
The first identified ALS-associated gene. Mutations typically result in a toxic gain-of-function in superoxide dismutase, triggering oxidative stress and mitochondrial dysfunction in motor neurons.
Encodes the TDP-43 protein, which undergoes pathological mislocalization and aggregation in over 90% of ALS cases and roughly half of FTD cases, disrupting RNA metabolism.
Encodes Fused in Sarcoma (FUS), a protein involved in RNA processing. Mutations are often associated with early-onset disease and juvenile forms of motor neuron degeneration.