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Open research questions in Amyotrophic Lateral Sclerosis Research

167 unresolved questions extracted from the limitations and future-work sections of 341 Amyotrophic Lateral Sclerosis Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • conducting large scale studies across diverse populations that investigate several variables in parallel with sufficient statistical power for each variable, - developing novel platforms and biomarkers to cover the full spectrum of NDDs

    Editorial: Biofluid biomarkers for the diagnosis of neurodegenerative diseases: current status · 2026 · DOI

  • the lack of effective therapies for neurodegenerative diseases - the need for disease-relevant biomarkers - the requirement for large-scale studies across diverse populations to investigate several variables in parallel with sufficient statistical power

    Editorial: Biofluid biomarkers for the diagnosis of neurodegenerative diseases: current status · 2026 · DOI

  • clinical evaluation of extended dosing intervals with RAG-17, - further studies to assess the safety and efficacy of RAG-17, - investigation of alternative strategies with potentially improved safety and dosing profiles

    Oligonucleotide–siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial · 2026 · DOI

  • The need for effective treatments for SOD1-ALS. The challenge of CNS delivery in RNAi therapeutics. The potential for improved safety and dosing profiles compared to existing treatments.

    Oligonucleotide–siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial · 2026 · DOI

  • The lack of curative treatments for ALS. The difficulty in definitive diagnosis due to non-specific symptoms and imaging findings. The need for reliable biomarkers to enable early, precise diagnosis and monitoring.

    Role and Potential of Artificial Intelligence in Biomarker Discovery and Development of Treatment Strategies for Amyotrophic Lateral Sclerosis · 2025 · DOI

  • While current therapeutic approaches are designed to individually target unique cryptic exons of TDP-43 such as UNC13A, the sufficiency of such a strategy to mitigate motor neuron disease remains unclear.

    Restoring multiple TDP-43 cryptic targets, but not solely Unc13a, rescues motor neuron disease · 2026 · DOI

  • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose genetic architecture and underlying molecular mechanisms remain incompletely understood, particularly in sporadic disease.

    Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk · 2026 · DOI

  • Prospective incorporation of cTnT into clinical trials and evaluation across broader neuromuscular differentials are warranted.

    Plasma cardiac troponin T as a marker of skeletal muscle involvement in amyotrophic lateral sclerosis · 2026 · DOI

  • Abstract Background Sleep disturbance is common in patients with amyotrophic lateral sclerosis (ALS), but its association with severe clinical outcomes remains insufficiently characterized.

    Association between PSQI and composite endpoints in ALS patients: a retrospective cohort study from China · 2026 · DOI

  • However, these principles are typically studied in isolation and it remains unknown how local vulnerability and network spreading interact to shape cortical atrophy.

    Network spreading and local biological vulnerability in amyotrophic lateral sclerosis · 2025 · DOI

  • BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with multifactorial pathophysiologic mechanisms, yet reliable CSF biomarkers for the diagnosis of ALS are lacking.

    CSF Aβ, Tau, Axonal, Synaptic, Glial, Neural, and Inflammatory Biomarkers in Patients With Sporadic Amyotrophic Lateral Sclerosis · 2025 · DOI

  • This study was limited by the inability to consider minor THIs not receiving hospital attendance.

    Hospital-Diagnosed Traumatic Head Injury and Associated Risk of Developing ALS · 2025 · DOI

  • BACKGROUND AND OBJECTIVES: Previous studies have suggested that traumatic head injury (THI) may be a risk factor of amyotrophic lateral sclerosis (ALS) development, yet the association remains unclear.

    Hospital-Diagnosed Traumatic Head Injury and Associated Risk of Developing ALS · 2025 · DOI

  • BACKGROUND AND OBJECTIVES: The genetic contribution to clinical heterogeneity in amyotrophic lateral sclerosis (ALS) remains poorly understood, particularly regarding the role of genes associated with other neurodegenerative disorders.

    Genetic Variants Associated With Neurodegenerative Disorders in Patients With Amyotrophic Lateral Sclerosis and Phenotypic Variability · 2025 · DOI

  • Nevertheless, little is known about early developmental effects or the systemic nature of TDP-43-mediated pathology.

    TDP-43-mediated amyotrophic lateral sclerosis: new/hidden insights from Drosophila · 2025 · DOI

  • Background: Neurodegenerative diseases (NDDs) are multifactorial disorders frequently associated with gut dysbiosis, oxidative stress, and inflammation; however, the pathophysiological mechanisms remain poorly understood.

    Specific Bacterial Taxa and Their Metabolite, DHPS, May Be Linked to Gut Dyshomeostasis in Patients with Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis · 2025 · DOI

  • However, the molecular details of how the domain of TDP-43 CTFs leads to condensation and cytotoxicity remain elusive.

    Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity · 2024 · DOI

  • Understanding of the mechanisms of phMN degeneration in ALS is limited, mainly because human experimental models to study phMNs are lacking.

    Generation of human iPSC-derived phrenic-like motor neurons to model respiratory motor neuron degeneration in ALS · 2024 · DOI

  • BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood.

    Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis · 2024 · DOI

  • Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior.

    Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis · 2024 · DOI

  • This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS.

    Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype · 2024 · DOI

  • DISCUSSION: DSP is extremely common and often underrecognized in this predominantly non-Hispanic Black, low-income population and leads to substantial disease burden.

    Prevalence and Risk Factors of Distal Symmetric Polyneuropathy Among Predominantly Non-Hispanic Black, Low-Income Patients · 2024 · DOI

  • BACKGROUND AND OBJECTIVES: Sleep dysfunction is common in patients with neurodegenerative disorders; however, its neural underpinnings remain poorly characterized in genetic frontotemporal dementia (FTD).

    Association of Changes in Cerebral and Hypothalamic Structure With Sleep Dysfunction in Patients With Genetic Frontotemporal Dementia · 2024 · DOI

  • Despite extensive research, the etiology of ALS remains elusive, and effective treatment options are limited.

    Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives · 2024 · DOI

  • The possibility that some recordings may have originated from interneurons cannot be excluded. The spread of passive properties in the data did not suggest a separation between cell types. The soma of MNs in all groups aggregated into clusters, preventing further measurements and analysis at Day 60.

    Dynamic changes in excitability and viability of sporadic and SOD1-related amyotrophic lateral sclerosis iPSC-derived motor neurons · 2026 · DOI

Most-cited papers in Amyotrophic Lateral Sclerosis Research

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167 open questions have been extracted from the limitations and future-work passages of 341 Amyotrophic Lateral Sclerosis Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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