Open research questions in Amyotrophic Lateral Sclerosis Research
808 gap statements mined from Amyotrophic Lateral Sclerosis Research papers in our 7.9M-paper local library, which holds 2,709 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
One challenge is the limited availability of PSG for assessing nocturnal respiratory function in ALS patients. Another challenge is the need for individualized NIV titration and interface optimization to ensure adherence and therapeutic benefit. The paper also notes the challenge of detecting early signs of respiratory dysfunction in ALS patients before significant daytime symptoms develop.
Noninvasive ventilation in patients with amyotrophic lateral sclerosis: Is home sleep apnea testing a useful tool for initiating noninvasive ventilation? · 2026 · DOIThe molecular mechanisms underlying the relationship between HIPK2 and TDP-43 are not well understood. The role of HIPK2 in regulating TDP-43 subcellular distribution is not clear. The implications of HIPK2 loss for neurodegenerative disorders are not fully understood.
HIPK2 loss promotes TDP-43 cytoplasmic mis-localization through MAPK-pathway and is associated with TDP-43 proteinopathy in vivo · 2026 · DOIThe limited sample size of the study, which may impact the generalizability of the findings. The complexity of integrating multiple omics datasets to identify potential disease-associated processes and biomarkers. The need to carefully evaluate potential confounders, such as smoking status, that may influence epigenetic mechanisms.
A multi-omics study on monozygotic twins discordant for amyotrophic lateral sclerosis and literature review underline a potential role for innate immunity and epigenetic dysregulation in disease mechanisms · 2026 · DOIThere is a need to investigate the phenotypic variability related to mutations in different regions of the KIF5A gene.
KIF5A and ALS: a clinical and genetic description of a case series and review of literature · 2026 · DOIFurther studies are needed to confirm the effectiveness of the CBIT2 treatment in a larger population. Research is needed to fully understand the mechanisms by which the CBIT2 treatment works. Studies should investigate the potential for the CBIT2 treatment to be used in combination with other therapies. More research is needed to determine the long-term effects of the CBIT2 treatment.
Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular–Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report · 2025 · DOIThere is a lack of treatments capable of restoring lost neurological function. Neurological disorders will not only cause disability but also lead to death in the absence of effective therapies. The current therapies for ALS are unable to reverse the disease.
Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular–Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report · 2025 · DOIThe molecular mechanisms underlying neuronal and glial cell morphogenesis remain to be understood. The role of Rab11a in neuronal cell morphological differentiation is not well established. The relationship between C9orf72 and Rab11a in regulating neuronal morphological differentiation is not fully understood.
Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1 · 2024 · DOIUncertainty exists over the role of oxidative stress and inflammation in the development of neurodegenerative diseases. The exact mechanism of action of certain drugs, such as Riluzole, is still unknown. Further research is needed to understand the complex interplay between oxidative stress and inflammation in neurodegenerative diseases.
New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases · 2024 · DOITDP-43 pathology has been linked to extracellular TDP-43 species, association with the ER luminal oxidoreductase PDI, and ER stress-related phenotypes, yet whether TDP-43 fragments can directly access the ER lumen remains unclear.
Investigating Translocation Mechanisms of TDP ‐43 Into the Endoplasmic Reticulum Using Budding Yeast Models · 2026 · DOIAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor system degeneration, yet its white matter (WM) functional pathophysiology remains underexplored.
White Matter Functional Dysregulation in Amyotrophic Lateral Sclerosis: Machine Learning-Based Biomarkers and Transcriptomic Signatures · 2026 · DOIMultiple regulated cell death pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis, lysosomal cell death, autophagy-dependent cell death, NETosis, and other emerging cell death modalities, have been implicated in ALS, but their mechanistic interactions and relative contributions remain poorly understood.
Therapeutic Implications of Cell Death Pathways Across the Course of Amyotrophic Lateral Sclerosis · 2026 · DOIThese findings highlight the propensity of hnRNP K mislocalisation in neurodegenerative diseases and the aged brain and underscore the need for further investigation into its functional consequences.
Widespread hnRNP K Mislocalisation Suggests Differential Neuronal Vulnerability in the Neurodegenerative and Ageing Human Brain · 2026 · DOIHowever, the broader distribution of hnRNP K mislocalisation across different brain regions, other diseases and its pathological significance remains unclear.
Widespread hnRNP K Mislocalisation Suggests Differential Neuronal Vulnerability in the Neurodegenerative and Ageing Human Brain · 2026 · DOIAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; the precise pathogenesis of sporadic ALS (sALS) has not yet been elucidated up to now.
5‐Hydroxytryptamine Distribution Alteration in Both Neuron and Synapse of Tg( SOD1 * G93A )1gur Mice: A Potential Intervention Candidate Strategy for Amyotrophic Lateral Sclerosis · 2026 · DOIThis study aimed to depict the research landscape of C9orf72 in FTD over the past decade, track emerging research hotspots, and provide insights into under-researched areas.
A Decade of Research on C9orf72 in Frontotemporal Dementia (2014-2024): A Bibliometric Analysis of Global Trends and Hotspots · 2025 · DOISeveral variants of sequestosome 1 (SQSTM1) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype–phenotype correlation remains unclear.
Genotype–phenotype correlation of SQSTM1 variants in patients with amyotrophic lateral sclerosis · 2024 · DOIHowever, the nature of network-level impairment in the pre-motor activity in ALS remains unclear.
Abnormal EEG Spectral Power and Coherence Measures During Pre-Motor Stage in Amyotrophic Lateral Sclerosis · 2024 · DOIObservational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear.
Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis · 2024 · DOIFew studies have examined the long-term effects of lung volume recruitment (LVR) in amyotrophic lateral sclerosis (ALS).
Lung Volume Recruitment Slows Pulmonary Functional Decline and Prolongs Survival in ALS · 2025 · DOIFurther studies should attempt to delineate the risk of psychiatric disorders in C9orf72 kindreds, - Collaborations between neurology and psychiatry are necessary for clinical decision making and genetic counseling, - Larger epidemiologic studies are needed to confirm the association between ALS and psychiatric…
Future research should assess RTXMB's long term effectiveness, safety, and clinical transitional potential in ALS, - More research into combination methods, molecular processes, and optimal dose may strengthen its therapeutic…
Combined rituximab and magnesium acetyl taurate therapy attenuates neurodegeneration via ERK/c-JNK/P38MAPK signaling modulation in methylmercury-induced amyotrophic lateral sclerosis-like neurotoxicity · 2026 · DOIFurther studies on the role of OS and inflammation in NDDs - Investigation of the exact mechanism of action of Riluzole - Analysis of the principal past and actual clinical…
New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases · 2024 · DOIInvestigate the effects of therapies on gut microbiota, - Examine the role of gut-derived toxins in ALS pathogenesis, - Study the relationship between gut dysbiosis…
Investigate the effects of Rab11a knockdown on other cell types, - Investigate the long-term effects of hesperetin treatment, - Explore the potential therapeutic applications of hesperetin in neurological diseases, - Investigate the role of Rab11b downstream…
Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1 · 2024 · DOIThe review highlights the importance of further research on biomarkers aimed at improving the diagnosis, treatment, and development of drugs for ALS.
Unraveling the Pathological Mechanisms and Biomarkers of Amyotrophic Lateral Sclerosis: A Comprehensive Review · 2026 · DOI
Most-cited papers in Amyotrophic Lateral Sclerosis Research
- Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis · Science · 2006 · 5,962 citations
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis · Nature · 1993 · 5,551 citations
- Motor Neuron Degeneration in Mice that Express a Human Cu,Zn Superoxide Dismutase Mutation · Science · 1994 · 3,517 citations
- Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis · Science · 2009 · 2,309 citations
- Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6 · Science · 2009 · 2,302 citations
- TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis · Science · 2008 · 2,276 citations
- A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis · New England Journal of Medicine · 1994 · 1,847 citations
- Amyotrophic Lateral Sclerosis · New England Journal of Medicine · 2017 · 1,787 citations
- Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases · Acta Pharmacologica Sinica · 2009 · 1,119 citations
- Dose-ranging study of riluzole in amyotrophic lateral sclerosis · The Lancet · 1996 · 1,032 citations
Most recent work
- Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis · JAMA Neurology · 2026
- Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis · Nature Genetics · 2026
- Blocking RAN translation without altering repeat RNAs rescues C9ORF72 -related ALS and FTD phenotypes · Science · 2026
- Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains · Molecular Cell · 2026
- Plasma proteomic signatures of cellular aging predict human disease · Nature Medicine · 2026
- Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders · bioRxiv · 2026
- Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction · Science Translational Medicine · 2026
- Plasma NfL, GFAP and pTau181 define distinct biological axes in amyotrophic lateral sclerosis · Neurobiology of Disease · 2026
- Long-Term Exposure to Air Pollution and Risk and Prognosis of Motor Neuron Disease · JAMA Neurology · 2026
- Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions · Cells · 2026
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