Amyotrophic lateral sclerosis (ALS), often recognized as the most prevalent motor neuron disease, is a devastating neurodegenerative condition typically leading to fatality within 2–5 years following the onset of symptoms. While ALS incidence is largely consistent globally, there’s evidence suggesting an increase in recent decades. Despite advancements in genetic research, which have illuminated the causes of ALS, particularly in familial cases, non-genetic factors are increasingly recognized as significant contributors requiring further investigation. Understanding the typical age of diagnosis is crucial in recognizing and managing this disease.
ALS is characterized by the degeneration of motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy. The disease progresses to widespread paralysis, eventually affecting respiratory muscles and leading to respiratory failure, a common cause of death in ALS patients. While the average survival post-diagnosis is short, a subset of patients lives for a decade or longer.
Recent perspectives broaden ALS beyond a motor neuron-specific disease, recognizing it as a multisystem disorder. Extramotor symptoms, including cognitive deficits and, in some cases, frontotemporal dementia (FTD), are observed in a significant portion of ALS patients, highlighting the clinical, pathological, and genetic overlap between ALS and FTD. The connection to dementia extends beyond FTD, with studies indicating a higher dementia risk within ALS patient families, especially those with C9ORF72 gene mutations.
Familial ALS, accounting for 10%–15% of cases, is defined by a family history of the disease. Sporadic ALS, with no familial link, is more common. The incidence of sporadic ALS in Western countries ranges from 1 to 2 per 100,000 annually, with a lifetime risk of approximately 1 in 400. The average age of diagnosis for sporadic ALS is between 58 and 63 years, while familial ALS tends to present earlier, between 40 and 60 years. The disease is rare before age 40, with incidence rising sharply with age, peaking in the 70-79 age group. Men are more susceptible to ALS than women, with a male-to-female ratio of 1.2–1.5. The reported increase in ALS incidence in several countries necessitates ongoing research to differentiate between a true rise and factors like increased awareness and improved diagnostic practices.
Geographic clusters of ALS, notably the Western Pacific form in Guam and Japan, exhibit prevalence rates 50–100 times higher than elsewhere. This ALS-Parkinson’s dementia complex (ALS-PDC) presents in various forms, and its etiology remains unclear, though prevalence is reportedly declining.
Currently, there is no cure for ALS. Riluzole, the only FDA-approved drug for ALS, offers modest survival extension, potentially more effective in early stages or younger patients.
Risk Factors and the Age of ALS Diagnosis
While several factors have been implicated in ALS, established risk factors include older age, male sex, and family history. This section delves into frequently studied risk factors, emphasizing their potential connection to the average age of ALS diagnosis.
Familial Aggregation and Genetic Predisposition
Family studies underscore the heritable aspect of ALS. Individuals with ALS family history face a significantly elevated risk. Twin studies further support this, estimating ALS heritability at around 61%. Genetic factors play a critical role, particularly in familial ALS, and influence the age of onset. Familial ALS often presents at a younger age compared to sporadic forms, highlighting the impact of genetic mutations on disease manifestation.
Key Genetic Risk Factors and Their Influence on Age
Genetic research has identified several genes strongly associated with ALS. Mutations in genes like C9ORF72 and SOD1 are major contributors to familial ALS and also present in some sporadic cases.
C9ORF72 Gene
Mutations in the C9ORF72 gene are a leading genetic cause of both ALS and FTD. This gene, located on chromosome 9, features a hexanucleotide repeat expansion. In ALS patients, the number of repeats is vastly increased compared to healthy individuals. This mutation is prevalent in familial ALS and also contributes to sporadic ALS cases. The C9ORF72 mutation’s impact on the average age of diagnosis is noteworthy, with some studies suggesting a slightly younger age of onset in carriers, although this is an area of ongoing research.
SOD1 Gene
Mutations in the SOD1 gene are another significant genetic factor in ALS. SOD1 is crucial for neutralizing superoxide radicals. Over 170 SOD1 mutations have been linked to ALS. These mutations predominantly exhibit dominant inheritance, except for the D90A mutation. Research indicates that SOD1 mutations lead to a toxic gain of function, contributing to motor neuron degeneration. Similar to C9ORF72, the specific SOD1 mutation might influence the age of diagnosis, but more research is needed to establish clear correlations.
TARDBP Gene
The TARDBP gene encodes TDP-43, a protein involved in DNA and RNA binding. Mutations in TARDBP are found in both familial and sporadic ALS. Mutated TDP-43 leads to abnormal protein accumulation in motor neurons. While TARDBP mutations are linked to ALS, their direct effect on the average age of diagnosis isn’t as clearly defined as with C9ORF72 and SOD1, warranting further study.
Lifestyle Risk Factors and Potential Age-Related Effects
Lifestyle choices have been explored as potential risk modifiers for ALS. Understanding how these factors might interact with age is important.
Smoking
Smoking is considered a probable risk factor for ALS, particularly in women, especially post-menopausal women. The relationship between smoking and the age of ALS diagnosis is complex. Some studies suggest that smoking might lead to an earlier onset in susceptible individuals, but further research is needed to clarify this age-related aspect.
Dietary Factors: Antioxidants
Dietary factors, especially antioxidants like vitamin E, have been investigated for their potential protective role against ALS. Higher antioxidant intake is associated with a lower ALS risk in some studies. While diet’s influence on the average age of diagnosis isn’t directly established, a diet rich in antioxidants might potentially delay onset in some individuals by mitigating oxidative stress, a factor in neurodegeneration.
Body Mass Index (BMI) and Physical Fitness
Lower BMI and higher physical fitness levels have been observed in ALS patients. Interestingly, high physical fitness in early adulthood has been linked to a higher later-life ALS risk in some studies. Low BMI is also a prognostic indicator post-diagnosis. Premorbid BMI seems to influence ALS risk and mortality. The connection between BMI, fitness, and age of diagnosis is complex and requires more research. It’s unclear if these factors directly shift the average age of onset or primarily affect disease progression after diagnosis.
Athleticism, Head Trauma, and Physical Exercise
The case of Lou Gehrig highlighted a possible link between athleticism and ALS. Increased ALS risk has been reported in athletes, particularly football and soccer players, and individuals with vigorous physical activity. Head injuries, performance-enhancing drugs, and field chemicals have been proposed as contributing factors. Chronic traumatic encephalopathy, resulting from repeated head injuries, is also considered in athletes with neurodegenerative conditions. The type and intensity of physical activity (professional vs. recreational) may have differing effects. While athleticism is intriguing, more data is needed, given the small case numbers in studies. It’s not clear if athletic activity directly impacts the average age of diagnosis or if it’s more related to triggering the disease in susceptible individuals, potentially at any age.
Occupational and Environmental Risk Factors and Age
Occupational and environmental exposures are investigated as potential ALS risk factors. The age at which these exposures occur and their cumulative effect might be relevant to the average age of diagnosis.
Occupational Exposures
Various occupations, including those involving exposure to chemicals, pesticides, metals, and electromagnetic fields (EMF), have been linked to altered ALS risk. Military personnel, exposed to unique stressors and toxins, are also studied. It’s challenging to pinpoint common risk factors across diverse occupations. The age of exposure in these occupations and the duration might influence when ALS is diagnosed, but this is not well-established.
Electromagnetic Fields (EMF) and Electrical Exposures
“Electrical” occupations, especially welding, have been associated with ALS. Exposure to EMF, electric shocks, and magnetic fields are considered. The link between EMF and ALS is generally weaker than that of electrical occupations. Whether electric shocks or EMF exposure is the key factor remains unclear. Meta-analyses suggest a slight ALS risk increase in high-EMF occupations. Residential EMF exposure studies are less conclusive. Occupational EMF exposure, typically occurring during working age, might contribute to ALS development and diagnosis later in life, potentially affecting the average age of diagnosis in specific occupational groups.
Metals: Lead, Manganese, Iron, Selenium, and Others
Lead exposure is a long-standing hypothesis in ALS etiology. Studies have shown associations between lead levels and ALS. Manganese, known for neurotoxicity, is elevated in CSF of ALS patients, particularly in welders exposed to manganese. Iron accumulation in the brain is also implicated in neurodegeneration, with increased iron reported in specific brain regions of ALS patients. Selenium and other metals like copper, aluminum, and arsenic are also under investigation. The age of exposure to these metals, especially occupational exposure, and their accumulation over time could be factors influencing the age of diagnosis, though direct links are still being researched.
Pesticides
Pesticide exposure is widely studied in relation to ALS. Associations between pesticide use and ALS have been suggested in multiple studies and meta-analyses. Some studies suggest a male-specific association. Long-term pesticide exposure, which can start at various ages depending on occupation or environment, might contribute to ALS risk and potentially influence the average age of diagnosis, depending on the latency period and cumulative exposure.
β-methylamino-L-alanine (BMAA)
BMAA exposure is linked to the high ALS-PDC incidence in the Western Pacific. BMAA is produced by cyanobacteria and can accumulate in the food chain. Studies found higher BMAA levels in brain and spinal cord tissues of ALS patients. Environmental exposure to BMAA, potentially starting from a young age, may contribute to neurodegeneration and influence the age of diagnosis, especially in regions with high BMAA exposure.
Viruses
Viral infections are considered as potential ALS risk factors. Enteroviruses and herpesviruses have been implicated. Retroviruses and endogenous retroviruses are also under investigation. Viral infections at different ages might initiate or accelerate neurodegenerative processes, potentially affecting the average age of ALS diagnosis, but the mechanisms and specific viruses involved require further research.
Medical Conditions and Their Relation to ALS Onset
Pre-existing medical conditions and medical history are being examined for links to ALS.
Head Trauma
Head trauma history has been associated with ALS in early studies. Later studies aimed to minimize bias by using objective assessments and excluding recent traumas. Severe head traumas may not be strongly linked, but the role of milder, repeated head traumas is less clear. Head trauma at any age could potentially trigger or accelerate neurodegenerative processes, possibly influencing the age of ALS diagnosis, particularly if there’s a latency period between trauma and symptom onset.
Metabolic Diseases: Diabetes
Metabolic disorders and ALS are being studied, particularly given the hypermetabolic state in ALS patients. Type 2 diabetes has been inversely associated with ALS risk, while type 1 diabetes might be a risk factor. Medications for metabolic disorders are also under investigation. The interplay between metabolic health, age, and ALS risk is complex. Type 2 diabetes, often diagnosed at older ages, showing an inverse association with ALS, which also typically diagnoses at older ages, suggests a complex relationship that might indirectly affect the average age of diagnosis for ALS. Type 1 diabetes, diagnosed earlier in life, showing a positive association with ALS, might suggest different mechanisms at play across the lifespan.
Cancer
The relationship between cancer and neurodegenerative diseases is complex, with some theories suggesting an inverse relationship in general. Earlier studies suggested a possible positive association between ALS and cancer, but most epidemiological studies refute this, except possibly for melanoma. Recent large-scale studies also refute a general link. Cancer and ALS are both age-related diseases, but their direct interaction concerning the average age of ALS diagnosis is not well-supported by current evidence, with most studies suggesting no clear link.
Neuroinflammation
Neuroinflammation is increasingly recognized in ALS pathology. Early ALS symptoms can mimic inflammatory neuromuscular diseases, potentially leading to misdiagnosis. Co-occurrence of ALS and multiple sclerosis has been noted in C9ORF72 mutation carriers, suggesting biological overlaps with autoimmune/inflammatory conditions. Chronic inflammatory conditions, which can develop at various ages, might interact with neurodegenerative processes and potentially influence the age of ALS diagnosis, although more research is needed to establish clear links.
Interactions Between Genetic and Non-genetic Factors and Age
The interplay between genes and environment is crucial in ALS. Even with highly penetrant mutations, not everyone develops ALS, indicating the role of modifying factors. Twin studies highlight non-genetic influences. Gene-environment interactions are increasingly studied in neurodegenerative diseases. These interactions can influence both ALS risk and potentially the age of diagnosis. For example, individuals with genetic predispositions might have their age of onset modified by environmental exposures like smoking or head trauma.
Future Directions in Understanding Age and Risk Factors in ALS
Classifying ALS subtypes based on clinical presentation, genetics, and pathology is critical for advancing research. Lack of subtype classification likely contributes to inconclusive findings regarding risk factors and treatment trials. A more holistic approach, studying multiple risk factors in concert, is needed to identify common pathways in motor neuron degeneration. Intensive evaluation of risk factors in case-control studies and longitudinal studies of high-risk populations (like family members of ALS patients) are promising strategies. Longitudinal data collection can reveal synergistic effects of different factors.
For individual risk factors like lead, a systemic approach measuring exposure across different body compartments (blood, CSF, bone) is essential. Understanding bone metabolism in relation to lead exposure is also important. Gene-environment interaction studies are crucial but challenging due to ALS rarity and the need for large-scale consortia. International consortia with deep genetic and epigenetic screening, combined with detailed environmental and lifestyle data, are vital for uncovering gene-environment interactions. Ensuring representativeness of ALS patients and standardized data collection across studies remains a challenge. Future case-control studies should consider using multiple control groups (population-based, disease controls, relatives) for more robust comparisons.
Conclusion: Age of Diagnosis and the Multifactorial Nature of ALS
Significant progress has been made in understanding ALS genetics and potential mechanisms. However, identifying non-genetic risk factors with certainty remains challenging. Improved knowledge of non-genetic risk factors, combined with genetic insights, is crucial for deciphering ALS causes and developing effective treatments. Understanding the average age of diagnosis in the context of these risk factors is a critical step towards earlier detection, risk stratification, and ultimately, finding a cure for this devastating disease. Recognizing the multifactorial etiology of ALS, encompassing both genetic predispositions and environmental influences throughout life, is essential for future research and clinical strategies.
Acknowledgments
The study was supported by the Swedish Research Council, the Swedish Society of Medical Research, and the Karolinska Institutet.
Footnotes
Disclosure
The authors report no conflicts of interest in this work.
