2 Critical Causes of ALS Doctors Want You to Know

ALS does not arrive with clear answers. For many people, it begins quietly, then unfolds into a diagnosis that changes everything. Across the world, hundreds of thousands of people are living with Amyotrophic Lateral Sclerosis, and each year, around 2 out of every 100,000 individuals are newly diagnosed. The numbers may seem small compared to other diseases, yet the impact is profound, reaching far beyond statistics into families, daily routines, and the way life is experienced.

What makes ALS especially unsettling is not just its progression, but how little is fully understood about why it begins. Many patients and families find themselves asking the same question again and again: what caused this? The search for answers becomes part of the journey, not only for peace of mind but also for a sense of control in an otherwise uncertain situation.

Doctors and researchers have spent years studying ALS, and while there is still much to uncover, certain causes and contributing factors have become clearer. Understanding these causes matters more than most people realize. It offers insight into risk, helps guide research, and brings a deeper awareness of how this condition develops. This article focuses on two critical causes of ALS that doctors believe you should understand. They may not explain every case, but they shed light on what is happening beneath the surface. Knowing them won’t change the past, but it can change how you see the condition and why awareness continues to matter so deeply.

Table of Contents

Primary Causes of ALS

The primary causes of Amyotrophic Lateral Sclerosis (ALS) are broadly divided into two classifications: familial, which is caused by inherited gene mutations, and sporadic, which is believed to result from a complex interaction between genetic susceptibility and environmental factors. For the vast majority of individuals diagnosed with ALS, a single, definitive cause cannot be identified.

Instead, the disease is understood to be multifactorial, meaning that multiple elements, both internal (genetic) and external (environmental), contribute to the progressive degeneration of motor neurons that characterizes the condition. This model helps explain why ALS can appear in individuals with no family history of the disease.

The scientific consensus is that while a small percentage of cases are purely genetic, most arise from a two-hit or multi-hit process where an underlying genetic predisposition makes a person vulnerable, and subsequent exposure to one or more environmental triggers initiates the disease cascade. The precise nature of these triggers and the specific genetic vulnerabilities they interact with are the subjects of intense and ongoing research worldwide, as unraveling this complex relationship is key to understanding, treating, and preventing ALS.

Two Main Types of ALS Based on Cause

The two main types of ALS based on their cause are sporadic ALS (sALS), which comprises 90-95% of all cases and occurs without any known family history, and familial ALS (fALS), which accounts for the remaining 5-10% of cases and is directly inherited due to a genetic mutation. This fundamental distinction is the starting point for investigating the origins of the disease in any given patient, although the lines between them are becoming increasingly blurred as research advances.

Sporadic ALS (sALS): This is by far the most common form of the disease. The term “sporadic” means that the disease appears to occur at random, with no clear association with family members or an obvious pattern of inheritance. The vast majority of people who develop ALS fall into this category. For these individuals, the cause is unknown but is strongly believed to be a multifactorial combination of subtle genetic predispositions and various environmental or lifestyle exposures encountered over a lifetime. The symptoms and disease progression of sALS are clinically indistinguishable from fALS; the only difference is the absence of a known family history.
Familial ALS (fALS): This form of the disease is inherited. In families with fALS, there is often a clear history of the disease affecting multiple generations. If a parent has the gene mutation for fALS, each of their children typically has a 50% chance of inheriting the same gene, a pattern known as autosomal dominant inheritance. Over 40 different genes have been identified that can cause fALS when mutated. However, even with a known genetic mutation, not everyone who inherits it will develop ALS, a concept known as incomplete penetrance. This suggests that even in clearly genetic cases, other factors may influence whether and when the disease manifests.

The Interaction of Genetic and Environmental Factors with Causes of ALS

Genetic and environmental factors are believed to interact to cause most cases of sporadic ALS through a multifactorial model, where an individual’s genetic makeup creates a predisposition that only progresses to disease after being activated by one or more environmental or lifestyle triggers. This concept, often called the gene-environment interaction hypothesis, is the leading explanation for why sALS develops in people without a direct inherited cause.

It posits that very few individuals are destined to develop ALS based on genetics alone; rather, a larger portion of the population carries “susceptibility genes” that slightly increase their risk. To illustrate this complex interaction, consider the following points:

The Loaded Gun Analogy: A common way to describe this model is the loaded gun and trigger analogy. In this scenario, a person’s genetic susceptibility is the loaded gun. By itself, it is dormant and may never cause harm. However, exposure to a specific environmental factor, such as a toxin, viral infection, or significant physical trauma, acts as the trigger that fires the gun, initiating the chain of cellular events that leads to motor neuron degeneration and the onset of ALS symptoms.
Threshold Model: Another way to conceptualize this is a threshold model. An individual might be born with several low-risk genetic variants. Each one alone is insignificant, but together they bring that person closer to a disease threshold. Throughout life, exposures to various environmental risk factors add to this burden. Once the cumulative burden from both genetic and environmental factors crosses a certain threshold, the disease process begins. This explains why ALS typically develops later in life, as it may take decades to accumulate enough hits to cross the threshold.
Explaining Sporadic Cases: This multifactorial hypothesis provides a powerful framework for understanding sporadic ALS. It explains why one person might be exposed to a potential toxin and remain healthy, while another person with a different genetic background develops ALS after the same exposure. It also helps account for the seemingly random nature of the disease, as the specific combination and timing of genetic and environmental factors required to trigger ALS could be unique to each individual. Research now focuses on identifying these susceptibility genes and environmental triggers to better predict risk and develop preventative strategies.

Genetic Factors to Be One of Causes of ALS

The known genetic factors that cause Amyotrophic Lateral Sclerosis (ALS) are mutations in specific genes, with the most significant being C9orf72, SOD1, TARDBP, and FUS, which are collectively responsible for the majority of familial ALS cases and are also implicated as risk factors in a subset of sporadic cases. Since the discovery of the first ALS-linked gene, SOD1, in 1993, the field of ALS genetics has exploded, with researchers now having identified over 40 genes associated with the disease.

These genetic discoveries have been instrumental in confirming that ALS is not a single disease but rather a clinical syndrome with multiple underlying molecular causes. While these gene mutations are the direct cause of most familial ALS cases, it is crucial to understand that their presence does not always guarantee the disease will manifest. This phenomenon, known as incomplete penetrance, suggests that even in cases with a strong genetic driver, other genetic or environmental modifiers may play a crucial role in determining the onset and progression of the illness.

The study of these genes has provided invaluable insights into the biological pathways that go awry in ALS, such as protein aggregation, RNA metabolism, and cellular waste disposal, paving the way for the development of targeted genetic therapies. Next, a closer examination of the most common mutations and their role in both familial and sporadic disease provides a clearer picture of the genetic landscape of ALS.

Common Gene Mutations Linked to Familial ALS

The most common gene mutations linked to familial ALS are found in four primary genes: C9orf72, SOD1, TARDBP, and FUS, with mutations in the C9orf72 gene representing the single most frequent genetic cause in individuals of European ancestry. Together, these four genes account for approximately 60-70% of all familial ALS cases, though dozens of other genes have been identified that contribute to the remaining percentage. Each of these genes disrupts normal cellular function in a unique way, highlighting the diverse molecular pathways that can lead to motor neuron death.

C9orf72 (Chromosome 9 Open Reading Frame 72): Discovered in 2011, a mutation in this gene is the most common known cause of both familial ALS and familial frontotemporal dementia (FTD), and it can cause a combination of both disorders. The mutation is not a typical change in the gene’s code but rather an abnormal expansion of a six-nucleotide sequence (GGGGCC) that repeats hundreds or even thousands of times, when it should only repeat less than 30 times. This expansion is thought to cause disease through three primary mechanisms: loss of normal protein function, production of toxic RNA molecules that sequester important proteins, and generation of abnormal “dipeptide repeat” proteins that clump together and damage neurons. It accounts for 30-40% of familial ALS cases in European populations.
SOD1 (Superoxide Dismutase 1): This was the first gene discovered to be associated with ALS. It provides instructions for making an enzyme that is crucial for breaking down toxic superoxide radicals, which are byproducts of normal cellular metabolism. Mutations in SOD1 are believed to result in a toxic gain-of-function, where the mutated protein becomes misshapen, clumps together into aggregates, and damages motor neurons through mechanisms like oxidative stress and mitochondrial dysfunction. SOD1 mutations account for approximately 10-20% of familial ALS cases and are the target of some of the first successful gene-targeting therapies.
TARDBP and FUS: These genes code for proteins (TDP-43 and FUS, respectively) that are vital for processing RNA, the molecular blueprint used to create proteins. When mutated, these proteins mislocalize from the cell nucleus to the cytoplasm, where they aggregate into toxic clumps. This disrupts normal RNA metabolism and protein production, ultimately leading to cell death. Intriguingly, abnormal clumps of the TDP-43 protein are a pathological hallmark found in the motor neurons of over 97% of all ALS patients, including sporadic cases, placing it at the center of ALS pathology even when the TARDBP gene itself is not mutated.

Can Genetic Factors Also Play a Role in Sporadic ALS?

Genetic factors can and do play a significant role in sporadic ALS (sALS), both through the presence of known ALS-causing gene mutations in individuals without a family history and through the influence of other risk-variant genes that increase a person’s susceptibility to the disease. The traditional distinction between purely genetic (familial) and purely environmental (sporadic) ALS is now considered an oversimplification.

Modern genetic sequencing has revealed that up to 10% of individuals diagnosed with sALS actually carry a high-impact mutation in one of the genes typically associated with familial ALS, such as C9orf72 or SOD1. This can happen if the gene mutation arose spontaneously (a de novo mutation) or if previous family members who carried the gene did not live long enough to develop symptoms (incomplete penetrance). Beyond these clear-cut mutations, the concept of genetic susceptibility is central to understanding the origins of the remaining sALS cases.

Genetic Susceptibility (Risk Variants): Most people with sALS do not have a single, powerful gene mutation that causes the disease. Instead, they are thought to have a collection of common genetic variants, each of which confers a very small amount of risk on its own. When a person inherits a specific combination of these low-impact variants, their cumulative effect can create a genetic predisposition or a heightened vulnerability to ALS. These are not disease-causing genes but rather susceptibility factors that lower the threshold for the disease to be triggered by environmental or lifestyle factors. An example is a variant in the ATXN2 gene, which, while not a direct cause, has been consistently shown to increase the risk of developing ALS.
Bridging Familial and Sporadic ALS: The discovery of genetic links in sporadic cases has fundamentally changed how researchers view the disease. It suggests that ALS exists on a spectrum, with purely monogenic (single-gene) familial cases at one end, purely environmental cases (if they exist) at the other, and the vast majority of sporadic cases lying somewhere in between, driven by a complex interplay of multiple genetic and non-genetic factors. This understanding reinforces the multifactorial hypothesis and underscores the importance of studying the genetics of all ALS patients, not just those with a family history, to fully unravel the disease’s complex origins.

Environmental Factors to Be One of Causes of ALS

The environmental factors suspected to increase the risk of developing Amyotrophic Lateral Sclerosis (ALS) include a range of exposures such as specific toxins like heavy metals and pesticides, lifestyle factors like cigarette smoking, and demographic associations like a history of military service. While the genetic underpinnings of ALS are becoming clearer, particularly for familial cases, the environmental triggers that may initiate the disease in genetically susceptible individuals remain largely elusive and are a source of intense scientific investigation.

The evidence for these factors comes primarily from epidemiological studies, which compare rates of ALS in populations with and without certain exposures. These studies can identify strong associations or correlations, but they often struggle to prove direct causation. The challenge lies in the long latency period of ALS as it can take decades between an exposure and the onset of symptoms and the fact that most people have a multitude of exposures throughout their lives, making it difficult to isolate a single culprit.

Despite these challenges, several compelling risk factors have emerged from decades of research, providing crucial clues into the non-genetic contributors to this complex disease.

Specific Environmental Exposures to Be ALS Cause

Specific environmental exposures that are considered potential risk factors for ALS include occupational and environmental toxins like lead and pesticides, lifestyle habits such as cigarette smoking, and possible exposure to cyanobacterial neurotoxins like BMAA. The evidence supporting each of these risk factors varies, with some having more consistent support across multiple studies than others.

It is widely believed that no single exposure causes ALS, but rather that cumulative or repeated exposures, particularly in genetically vulnerable individuals, may contribute to the disease process. The evidence for these key exposures can be broken down as follows:

Heavy Metals and Chemicals

A significant body of research has linked exposure to certain heavy metals and agricultural chemicals with an increased risk of ALS.

Lead: Numerous studies have shown a correlation between long-term lead exposure, often from occupations like welding or soldering, and a higher incidence of ALS. Lead is a known neurotoxin, and it is hypothesized that it can promote oxidative stress and protein aggregation, two key pathological features of ALS.
Pesticides and Herbicides: Individuals working in agriculture have been found to have a higher risk of developing ALS. This has led to investigation into specific chemicals, such as the pesticides organochlorine and pyrethroids, as potential triggers. These chemicals are designed to be neurotoxic to insects and may exert similar damaging effects on human motor neurons over time.

Cigarette Smoking

Smoking is one of the most consistently identified lifestyle risk factors for ALS. Multiple large-scale studies have demonstrated that current or former smokers have a significantly higher risk of developing the disease compared to non-smokers. The risk appears to be dose-dependent, meaning the more a person smokes, the higher their risk. Tobacco smoke contains thousands of chemicals, including numerous neurotoxins and compounds that induce oxidative stress, which are plausible mechanisms for how smoking could contribute to motor neuron damage.

Cyanobacterial Toxin (BMAA)

One of the more intriguing but also controversial hypotheses links ALS to beta-methylamino-L-alanine (BMAA), a neurotoxin produced by cyanobacteria (blue-green algae). This theory gained traction from observations of unusually high clusters of an ALS-like disease in Guam, where locals consumed cycad seeds and flying foxes that had bioaccumulated BMAA. Researchers have since detected BMAA in the brains of ALS patients from other regions, suggesting a possible link to exposure through contaminated water or food sources. However, the causal role of BMAA remains a subject of active debate and research.

The Evidence Linking Military Service to An Increased Risk of ALS

The evidence linking military service to an increased risk of ALS is strong, consistent, and officially recognized, with numerous large-scale studies demonstrating that military veterans are approximately 1.5 to 2 times more likely to develop the disease compared to the general population. This association is one of the most robust and well-established non-genetic risk factors for ALS.

The link is so compelling that, in 2008, the U.S. Department of Veterans Affairs (VA) designated ALS as a presumptive service-connected disease. This means that any veteran who served at least 90 consecutive days of active duty and later develops ALS is automatically eligible for disability and health benefits, regardless of where or when they served or what their specific duties were. This policy reflects the scientific consensus that something about the military experience significantly increases the risk for this neurodegenerative condition.

Exposure to Environmental Toxins: One prominent theory is that veterans are exposed to a unique combination of environmental toxins. This could include lead from firing ranges, chemicals in burn pits (particularly for veterans of the Gulf War and post-9/11 conflicts), pesticides and herbicides like Agent Orange (for Vietnam-era veterans), or other hazardous materials encountered during deployment or training.
Intense Physical Exertion and Trauma: Military service often involves extreme physical exertion, concussive injuries, and other physical trauma, all of which have been independently investigated as potential risk factors for ALS. It is possible that the combination of intense physical stress and repeated trauma could contribute to the neurodegenerative process in susceptible individuals.
Other Service-Related Factors: Researchers are also exploring other possibilities unique to military service, such as exposure to multiple vaccinations in a short period, infections encountered during deployment, or extreme psychological stress. It is highly probable that the increased risk is not due to a single factor but rather a multi-hit combination of several of these exposures and experiences that, together, create an environment conducive to the development of ALS in those with an underlying predisposition.

Advanced Theories and Diagnostic Methods Related to Causes of ALS

Genetic Testing

Genetic testing plays a crucial role in diagnosing Amyotrophic Lateral Sclerosis, particularly for individuals with a family history of the disease (familial ALS) or those with early-onset symptoms. The process typically begins with genetic counseling, where a specialist discusses the implications of testing, the potential results, and the psychological impact on the individual and their family.

If the individual proceeds, a blood or saliva sample is collected to perform a DNA sequence analysis. This analysis screens for mutations in genes known to be associated with ALS, such as C9orf72, SOD1, TARDBP, and FUS. Discovering a pathogenic mutation can confirm a genetic basis for the disease, providing a definitive answer for the patient and aiding in family planning for relatives who may want to understand their own risk.

For those with no family history (sporadic ALS), genetic testing can still identify a known mutation in up to 10% of cases, influencing prognosis and eligibility for gene-specific clinical trials. This genetic confirmation provides clarity not just for the patient but for the broader medical and research community.

Predictive Testing: Asymptomatic individuals with a known familial ALS mutation can undergo predictive testing to learn if they carry the gene, though this is a deeply personal decision with significant emotional consequences.
Therapeutic Development: Identifying specific genetic causes allows for the development of targeted therapies, such as antisense oligonucleotides designed to reduce the production of toxic proteins from mutated genes like SOD1.
Differential Diagnosis: In cases where symptoms are ambiguous, a positive genetic test can help differentiate ALS from other motor neuron diseases or neuromuscular mimics, leading to more appropriate and timely care.

Oxidative Stress

The theory of oxidative stress proposes that an imbalance between the production of damaging free radicals (also known as reactive oxygen species) and the body’s ability to neutralize them with antioxidants is a key contributor to motor neuron death in ALS. Motor neurons are highly active cells with significant energy demands, making them particularly vulnerable to the cellular damage caused by these unstable molecules.

When free radicals accumulate, they can attack and degrade vital cellular components, including proteins, lipids, and DNA. This cumulative damage impairs essential functions, such as energy production within the mitochondria, and ultimately triggers apoptosis, or programmed cell death. This process is believed to be a central mechanism in both genetic and sporadic forms of ALS.

For example, mutations in the SOD1 gene, one of the first genes linked to familial ALS, disrupt the function of an important antioxidant enzyme, directly leading to increased oxidative stress and subsequent neurodegeneration. Understanding this biochemical cascade is critical for developing neuroprotective strategies.

Mitochondrial Dysfunction: Mitochondria are the primary site of free radical production, and in ALS, they often become dysfunctional, creating a vicious cycle of increased oxidative stress and decreased cellular energy.
Environmental Links: Exposure to environmental toxins, such as heavy metals or certain pesticides, can also increase the body’s oxidative load, potentially acting as a trigger or accelerator for the disease process in genetically susceptible individuals.
Therapeutic Challenges: While the theory is strong, clinical trials of antioxidant supplements like Vitamin E have largely failed to show significant benefits in ALS patients, suggesting that more targeted or potent approaches are needed to effectively combat this process in the central nervous system.

ALS and Other Medical Conditions

Viral Infections vs. The Onset of ALS

The potential link between viral infections and the onset of ALS has been a subject of scientific investigation for decades, though a definitive causal relationship remains unproven. The hypothesis is primarily based on the fact that certain viruses, known as neurotropic viruses, can target and damage motor neurons. The most well-known example is the poliovirus, which causes a condition with symptoms similar to ALS.

Researchers have explored whether other viruses, particularly enteroviruses and human endogenous retroviruses (HERVs), could act as a trigger. The theory suggests that a virus could initiate the disease through a hit-and-run mechanism, causing initial damage and starting a cascade of neuroinflammation and degeneration that continues long after the virus is cleared.

Some studies have found fragments of viral RNA or an immune response to HERVs in the tissues of ALS patients, but these findings are not consistent across all studies and may represent a consequence of the disease rather than a cause. Currently, the scientific consensus is that if a virus does play a role, it is likely one of several factors in a complex, multi-step process.

Inflammatory Cascade: A viral infection could trigger a persistent inflammatory response in the central nervous system, creating a toxic environment that gradually damages motor neurons over time.
Genetic Predisposition: It is hypothesized that a viral trigger may only lead to ALS in individuals who have an underlying genetic susceptibility, explaining why only a tiny fraction of people exposed to common viruses develop the disease.
Lack of Conclusive Evidence: Despite extensive research, no single virus has been consistently isolated from ALS patients or proven to cause the disease, and antiviral therapies have not shown any efficacy in treating ALS.

ALS vs. Multiple Sclerosis (MS)

While both Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS) are debilitating neurodegenerative diseases, their underlying causes and primary risk factors are distinctly different. ALS is characterized by the death of motor neurons, leading to progressive muscle paralysis, whereas MS is an autoimmune disorder where the body’s immune system attacks the myelin sheath that protects nerve fibers in the central nervous system.

This fundamental difference in pathology is reflected in their risk profiles. ALS risk increases significantly with age, with a typical onset between 55 and 75, and it is slightly more common in men. Key risk factors include having a family history with specific gene mutations like C9orf72 or SOD1 and, to a lesser extent, a history of military service. In contrast, MS typically affects a younger population, with onset most common between the ages of 20 and 40, and it is two to three times more prevalent in women.

The risk factors for MS are strongly linked to environmental and immunological triggers, such as low Vitamin D levels, geographic location farther from the equator, and prior infection with the Epstein-Barr virus (EBV). These contrasting profiles guide diagnosis, research, and treatment strategies for each condition.

Genetic Basis: While both diseases have a genetic component, the specific genes involved are different. MS is strongly associated with variations in the HLA (human leukocyte antigen) gene complex, which regulates immune function, whereas ALS is linked to genes involved in RNA processing and protein degradation.
Disease Mechanism: The primary mechanism in ALS is neurodegeneration, where neurons die off. In MS, the primary mechanism is autoimmune-driven inflammation and demyelination, which disrupts nerve signal transmission.
Treatment Approach: Consequently, treatments for MS focus on modulating or suppressing the immune system to prevent attacks on myelin. In contrast, ALS treatments aim to slow the progression of neuron death, manage symptoms, and address mechanisms like excitotoxicity.

FAQs

1. What triggers ALS to start?

In most cases, ALS does not have a single clear trigger. It is believed to develop from a combination of genetic and environmental factors. Some individuals carry inherited gene mutations that increase risk, while others may be affected by long-term exposure to toxins, oxidative stress, or cellular damage within nerve cells. What makes ALS difficult to understand is that many people develop it without any obvious cause. This uncertainty is why research continues to focus on identifying the exact mechanisms behind how and why it begins.

2. What is the age of onset for ALS?

ALS most commonly appears between the ages of 40 and 70, with the average onset around the mid-50s. However, it can occur earlier, especially in rare genetic cases. Age remains one of the strongest risk factors, as the likelihood increases over time, even in individuals with no family history.

3. Who is most prone to ALS?

Certain groups appear to have a slightly higher risk. Men are more likely to develop ALS at younger ages, though the gap narrows later in life. Individuals with a family history of ALS or specific genetic mutations are at higher risk. Environmental exposure, such as contact with certain chemicals or heavy metals, has also been studied as a possible contributing factor. Still, many people diagnosed with ALS have no identifiable risk factors.

4. Is there any way to prevent ALS?

Currently, there is no proven way to fully prevent ALS. Maintaining overall health, reducing exposure to harmful substances, and supporting neurological health may be beneficial, but they do not guarantee prevention. The condition often develops without warning, making early awareness more important than prevention strategies alone.

5. How to test for ALS at home?

There is no reliable way to test for ALS at home. Diagnosis requires a comprehensive neurological evaluation, including clinical exams and specialized tests such as electromyography (EMG). If you notice persistent muscle weakness, coordination problems, or speech changes, it is important to seek medical attention rather than relying on self-assessment.

6. What foods to prevent ALS?

No specific food can prevent ALS. However, a balanced diet rich in antioxidants, healthy fats, and essential nutrients may support overall brain and nerve health. Foods such as leafy greens, berries, nuts, fish, and whole grains contribute to general well-being, but they are not a guaranteed protective factor against ALS.

Conclusion

Understanding the causes of ALS is about finding clarity in a condition that often feels unpredictable and overwhelming. While many questions remain unanswered, recognizing the two critical causes highlighted in this article offers a clearer picture of how ALS may begin and why it affects certain individuals. These insights remind you that ALS is not the result of a single choice or moment. It is a complex condition shaped by factors that are still being uncovered. That complexity can feel unsettling, yet it also drives ongoing research and hope for future breakthroughs.

Awareness remains one of the most powerful tools. The more you understand about ALS, the better prepared you are to recognize early signs, support ongoing research, and approach the condition with informed perspective. Knowledge may not change the diagnosis, but it changes how you respond to it and that can make a meaningful difference.

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Disclaimer

This article is intended for informational and educational purposes only. We are not medical professionals, and this content does not replace professional medical advice, diagnosis, or treatment.

The goal is to provide accurate, evidence-based information to raise awareness of causes of ALS. If you are experiencing persistent, severe, or concerning symptoms, you should seek guidance from a qualified healthcare provider.

2 Critical Causes of ALS Doctors Want You to Know