Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease that affects the nerve cells controlling voluntary muscle movement, leading to muscle weakness that worsens over time and eventually impacts the ability to move, speak, eat, and breathe.

Epidemiology

Amyotrophic lateral sclerosis is a relatively rare condition, though it affects thousands of people around the world. According to available data, approximately 5,000 people in the United States receive an ALS diagnosis each year^[3]. At any given time, there are around 30,000 people living with ALS in the United States^[5]. The lifetime risk of developing this disease is approximately 1 in 400 individuals^[5], which means that while it remains uncommon, it is not as rare as many people might think.

When researchers look at how often ALS appears in different populations, they find incidence rates ranging from 0.6 to 3.8 per 100,000 person-years. Interestingly, higher rates have been observed in Europe compared to Asian countries^[7]. The prevalence, which measures how many people are living with the disease at one time, ranges between 4.1 and 8.4 per 100,000 persons^[7]. These geographical differences may partly result from genetic factors and how thoroughly cases are identified and reported in different regions.

ALS is slightly more common in men than women, though recent studies suggest this difference may be decreasing over time^[6]. The disease is age-related, with most people finding out they have it when they are between 55 and 75 years of age^[6]. Some demographic variations exist as well. In the United States, European-Americans show more than double the prevalence compared to African-Americans^[7].

The number of ALS cases is expected to increase significantly in the coming decades. Projections suggest that cases will rise from 80,162 in 2015 to 105,693 in 2040 across ten studied countries and regions. This represents a 31% increase that cannot be explained by population growth alone, as the adult population in these areas is projected to grow by only 7.7%. Instead, population aging, particularly the expansion of the 60-79 age group most at risk for ALS, is likely driving this trend^[7].

Causes

The exact cause of amyotrophic lateral sclerosis remains largely unknown, which can be frustrating for patients and families seeking answers. What researchers do know is that the disease targets motor neurons, which are nerve cells in the brain and spinal cord that control voluntary muscle movement and breathing^[2]. As these motor neurons degenerate and die, they stop sending messages to the muscles, causing the muscles to weaken, twitch, and eventually waste away.

About 85% of all ALS cases are classified as sporadic ALS, which means they occur randomly with no known family history of the disease^[5]. The remaining 15% of cases are known as familial ALS, which can be inherited and runs in families^[5]. Even though sporadic cases don’t appear to run in families, genetic factors may still play a role in some instances.

When ALS is inherited, it involves specific genetic changes. About 70% of familial cases and 5% to 10% of sporadic cases involve gene changes^[3]. More than 40 genes have been associated with familial ALS. The most common known genetic mutation in ALS is in the C9orf72 gene, which accounts for approximately 30 to 40% of all familial ALS cases^[5]. These mutations are also known to cause Frontotemporal Dementia (FTD), another neurodegenerative disease that primarily affects behavior and the ability to think and reason. Mutations in the SOD1 gene comprise around 20% of familial ALS, while TARDBP and FUS gene mutations each account for about five percent of familial cases^[5].

Researchers believe that ALS likely results from a combination of genetic and environmental factors. There are many theories outlining potential causes, including oxidative stress, mitochondrial dysfunction, immune system overactivity, glutamate toxicity, and exposure to toxic substances^[5]. Some studies have suggested possible links with exposure to heavy metals such as lead and mercury, as well as trace elements, solvents, radiation, and agricultural chemicals, though no confirmed link has been definitively established^[6]. Exposure to toxins like lead or mercury, viruses, or trauma may also play a role^[3].

Risk Factors

Several factors can increase the likelihood of developing amyotrophic lateral sclerosis, though having a risk factor doesn’t guarantee that someone will develop the disease. Age is one of the most significant risk factors. People are most likely to develop symptoms between the ages of 45 and 75 years^[4], with the highest risk occurring between ages 55 and 75^[6].

Gender also plays a role in ALS risk, though this appears to be changing. Historically, ALS has been slightly more common in men than women, but recent studies suggest that this difference is decreasing over time^[6]. For familial ALS specifically, the disease is found equally among men and women^[6].

Having a family history of ALS increases the risk significantly. About 5 to 10% of ALS cases occur within families, meaning that two or more people in a family have ALS^[6]. These cases are caused by inherited genetic factors. If someone has a genetic cause for ALS, particularly a pathogenic variant in the SOD1 gene, there are implications for family members who may also carry the genetic change.

Military service has emerged as a notable risk factor for ALS. Studies have shown that people who have served in the military are almost twice as likely to develop ALS compared to the general population^[5]. This elevated risk applies to veterans, making it particularly important for this group to be aware of early symptoms and seek medical attention if they notice concerning changes.

While researchers have investigated many other potential risk factors, including diet, physical activity, and injury, no definite environmental factors have been confirmed as directly linked to ALS^[6]. Some studies have suggested possible connections with exposure to heavy metals, organic chemicals, smoking, electric shock, physical exercise, and head injury^[4], but more research is needed to understand these relationships clearly.

Symptoms

The symptoms of amyotrophic lateral sclerosis vary considerably from person to person, and they depend on which nerve cells are affected by the disease. ALS generally begins with muscle weakness that spreads and gets worse over time^[1]. Early symptoms can be subtle and easy to overlook, which sometimes delays diagnosis.

Common early symptoms include muscle twitches in the arm, leg, shoulder, or tongue. People may experience muscle cramps and notice that their muscles feel tight and stiff, a condition called spasticity^[2]. Muscle weakness affecting an arm, a leg, or the neck is another typical early sign. Some people develop slurred and nasal speech, while others first notice difficulty chewing or swallowing^[2].

ALS often starts in the hands, feet, arms, or legs, and then spreads to other parts of the body^[1]. This progression pattern means that symptoms affecting one area of the body will eventually affect other areas as well. Early symptoms might include trouble walking or doing usual daily activities, tripping and falling, weakness in the legs, feet, or ankles, and hand weakness or clumsiness^[1].

As the disorder progresses, muscle weakness and atrophy (wasting away of muscle) spread to other parts of the body. People with ALS may develop problems with chewing food and swallowing, a condition called dysphagia. Drooling, medically known as sialorrhea, can occur. Speaking or forming words becomes difficult, referred to as dysarthria. Breathing problems, called dyspnea, develop as the muscles needed for breathing weaken^[2].

Some people with ALS experience unintended crying, laughing, or other emotional displays, known as pseudobulbar symptoms^[2]. These emotional outbursts don’t necessarily reflect how the person actually feels and can be distressing for both the individual and their loved ones. Other symptoms that may develop include constipation, difficulty maintaining a healthy weight and getting enough nutrients, and significant fatigue^[2][3].

Eventually, people with ALS become unable to stand or walk, get in or out of bed on their own, use their hands and arms, or breathe on their own^[2]. Because they usually remain able to reason, remember, and understand, they are aware of their progressive loss of function. This awareness can cause anxiety and depression in the person with ALS and their loved ones.

There’s generally no pain in the early stages of ALS, and pain is also not common in the later stages^[1]. ALS doesn’t usually affect bladder control^[1], which differs from some other neurological conditions. The senses, including hearing, sight, smell, taste, and touch, are not affected by ALS. In most cases, memory and thinking are not affected either^[5], though some people may experience problems with language or decision-making, and some develop a form of dementia known as FTD-ALS^[2].

The speed at which symptoms progress varies considerably from person to person. Most people live from 2 to 5 years after symptoms develop^[6]. Most people with ALS die from being unable to breathe on their own, known as respiratory failure, usually within three to five years of symptoms first appearing. However, about 1 in 10 people survive for 10 years or more^[2].

Prevention

Unfortunately, because the exact causes of amyotrophic lateral sclerosis remain largely unknown, there are no proven strategies to prevent the disease entirely. Researchers have not identified specific lifestyle changes, vaccinations, or supplements that can reliably prevent ALS from developing. This lack of preventive measures reflects the complexity of the disease and the ongoing need for more research into its underlying causes.

For people with a known family history of ALS, genetic testing and counseling may be available. About 10% of ALS cases are familial, meaning they can be inherited^[5]. For people with a pathogenic variant in the SOD1 gene, there is an approved drug that has been shown to slow disease progression. Genetic testing can help identify individuals who carry specific gene mutations associated with ALS, which may allow for earlier monitoring and intervention if symptoms begin to appear.

While primary prevention remains elusive, early detection and prompt medical attention when symptoms first appear can potentially improve outcomes. Recognizing early symptoms such as muscle weakness, twitching, or difficulty with speech and swallowing, and seeking medical evaluation quickly, allows for earlier diagnosis and the possibility of starting treatments that may slow disease progression.

For veterans, who face an elevated risk of developing ALS, awareness of this increased risk and regular health monitoring may help catch the disease in its earlier stages. Although this doesn’t prevent the disease, it can lead to earlier interventions and access to support services.

Pathophysiology

The pathophysiology of amyotrophic lateral sclerosis involves complex changes in how the nervous system normally functions. At the core of the disease is the progressive degeneration and death of motor neurons. These specialized nerve cells are responsible for controlling voluntary muscle movements, including walking, talking, chewing, and breathing.

Motor neurons communicate with muscles by sending electrical and chemical messages. Think of this communication system like a telephone line connecting the brain to the muscles. In ALS, this communication system breaks down. The disease disrupts communication, like bad phone reception. The messages sent from neurons to muscles break up and don’t get through clearly. This eventually causes the call to end, and neurons can’t take any new calls, causing symptoms to appear^[3].

As motor neurons degenerate and die, they stop sending messages to the muscles. Without these signals, muscles can’t function properly. This causes the muscles to weaken and start to twitch, a phenomenon called fasciculations. Over time, the muscles waste away in a process called atrophy^[2]. Eventually, the brain loses its ability to start and control voluntary movements.

The progression of ALS involves complex neurological mechanisms that researchers are still working to fully understand. Key factors that appear to play a role include oxidative stress, which involves altered oxidative stress biomarker profiles that have been observed in ALS models and patient samples^[7]. Another factor is excitotoxicity, where motor neurons are particularly vulnerable to damage from excessive stimulation by certain chemical messengers in the brain.

The disease affects both upper motor neurons, which are located in the brain, and lower motor neurons, which are located in the spinal cord. Upper motor neuron involvement causes hyperreflexia (exaggerated reflexes), spasticity (muscle stiffness), and poor dexterity. Lower motor neuron degeneration results in muscle atrophy and fasciculations^[7]. The combination of both upper and lower motor neuron degeneration is what distinguishes ALS from other motor neuron diseases.

The pathophysiology also involves changes at the molecular and cellular level. Genetic mutations in genes like C9orf72, SOD1, TARDBP, and FUS can lead to abnormal protein production or function, which may contribute to motor neuron death. These proteins can accumulate in cells and disrupt normal cellular processes. Mitochondrial dysfunction, problems with the cellular structures that produce energy, also appears to play a role in motor neuron degeneration.

Immune system overactivity and inflammation in the nervous system may contribute to the progression of ALS. Additionally, glutamate toxicity, where excessive amounts of the neurotransmitter glutamate overstimulate neurons and lead to their death, is another mechanism being studied^[5].

The respiratory system eventually becomes affected as the muscles needed for breathing weaken. This respiratory involvement is what ultimately leads to respiratory failure, the most common cause of death in people with ALS. Understanding these pathophysiological mechanisms is crucial for developing new treatments and interventions that might slow or halt the progression of this devastating disease.