AAN 2026 — Amyotrophic Lateral Sclerosis

Dates: April 18-22, 2026 Location: McCormick Place, Chicago, Illinois Track: Motor Neuron Diseases and Neuromuscular Disorders

Overview

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Amyotrophic lateral sclerosis (ALS) remains a central focus at AAN 2026, with sessions covering the latest advances in genetic therapies targeting SOD1 and C9orf72, neurofilament biomarkers for patient stratification, trial design innovations, and symptomatic management. The field has seen a dramatic acceleration in therapeutic development, particularly with the approval and ongoing trials of antisense oligonucleotides (ASOs) and gene therapies. AAN 2026 will highlight the transition from purely symptomatic care to a disease-modifying era, while acknowledging the significant challenges that remain.

Genetic Forms and Targeted Therapies

SOD1 ALS

The approval of tofersen (Qalsody) for SOD1-mutant ALS represents a landmark in precision medicine for ALS^{1SOD1-targeted therapies in ALS2023 · N Engl J Med · PMID 36940640Open reference}:

• Tofersen (BIIB067): Updated data from the open-label extension (OLE) of the Phase 3 VALOR trial, showing sustained slowing of disease progression and reductions in CSF neurofilament light chain (NfL) over 52 weeks

• Early intervention: Data supporting initiation of tofersen in presymptomatic SOD1 mutation carriers, including the ATLAS study

• Combination strategies: Exploring tofersen with other neuroprotective agents (edaravone, AMX0035)

C9orf72 ALS

C9orf72 hexanucleotide repeat expansion is the most common genetic cause of familial ALS and FTD^{2C9orf72 ALS: phenotype and therapeutic targets2024 · Lancet Neurol · PMID 38522188Open reference}:

• ASO approaches: Several ASOs targeting C9orf72 transcripts are in preclinical and early clinical stages

• Gain-of-function vs. loss-of-function: Debate continues on whether the primary pathology is toxic repeat RNA, dipeptide repeat proteins, or C9orf72 haploinsufficiency

• Antisense strategies: BIIB078 (Wave Life Sciences) ASO data expected

• Gene therapy: AAV approaches to reduce toxic expansions

TDP-43 Pathology

Nearly all ALS cases (except FUS mutations) show TDP-43 proteinopathy^{3TDP-43 pathology in ALS and frontotemporal dementia2024 · Brain · PMID 38409623Open reference}:

• TDP-43 aggregation: Mechanistic studies on how misfolded TDP-43 spreads through the motor system

• Liquid-liquid phase separation: Role of stress granules and membraneless organelles in TDP-43 aggregation

• Therapeutic targets: Small molecules promoting TDP-43 solubility and clearance

• FUS mutations: Distinct pathology with FUS-positive inclusions, different from TDP-43

Clinical Trials

Recent Approvals and Ongoing Studies

The ALS therapeutic landscape has expanded significantly^{4ALS clinical trials: 2024 landscape2024 · Neurology · PMID 38567892Open reference}:

Platform Trial Designs

The HEALEY ALS Platform Trial represents a new paradigm:

• Master protocol with multiple active arms

• Shared placebo arm reduces patient exposure

• Adaptive randomization based on interim analyses

• Biomarker-driven enrollment criteria

• Results from additional arms expected at AAN 2026

Key Trial Endpoints

• ALSFRS-R slope: Primary functional endpoint, now including rate of change analysis

• Survival: Time to death or permanent ventilation

• Biomarker composites: NfL, creatinine,握力 as surrogate endpoints

• Neuroimaging: MRI and PET as progressive markers

• Electrical impedance myography: Non-invasive muscle assessment

Biomarkers

Neurofilament Light Chain (NfL)

NfL has become the cornerstone biomarker for ALS^{5Biomarkers in ALS: neurofilaments and beyond2023 · Ann Neurol · PMID 37012198Open reference}:

• Serum vs. CSF: High correlation between paired samples, enabling less invasive monitoring

• Prognostic value: Higher baseline NfL predicts faster progression

• Treatment response: Tofersen and other DMTs reduce NfL trajectories

• Trial enrichment: Using NfL to select patients more likely to progress during trial

• Pre-symptomatic: Elevated NfL in mutation carriers before symptom onset

Emerging Biomarkers

• Phosphorylated neurofilament heavy chain (pNfH): Complementary to NfL

• Urinary p75 ECD: Extracellular domain of p75, non-invasive sampling

• CSF chitinase-3-like protein 1 (YKL-40): Glial activation marker

• Proteomic panels: Machine learning-derived signatures

• Imaging: PET with translocator protein (TSPO) for microglia activation

Genotype-Specific Biomarkers

• SOD1: NfL trajectories and how they respond to tofersen

• C9orf72: Correlation of repeat length with NfL and clinical phenotype

• FUS: Different NfL kinetics compared to TDP-43 cases

Symptomatic Management and Care

Respiratory Management

• Non-invasive ventilation (NIV): Timing and titration

• Diaphragmatic pacing: Selected cases

• Cough assist devices: Preventing aspiration pneumonia

• Pulmonary function monitoring (FVC, Sniff Nasal Pressure)

Nutritional Support

• Early gastrostomy placement

• Caloric intake monitoring

• PEG vs. PIG (nasogastric) considerations

• Role of Mediterranean diet in ALS (MND-DIET trial)

Pharmacologic Symptom Management

• Cramps: Mexiletine, taurine, magnesium

• Spasticity: Baclofen, tizanidine, benzodiazepines

• Pseudobulbar affect: Dextromethorphan/quinidine, dextromethorphan alone

• Sialorrhea: Glycopyrrolate, botulinum toxin to salivary glands

• Fatigue: Modafinil

Specific Sessions and Symposia

Late-Breaking Results

• HEALEY Platform Trial: New arm results

• C9orf72 ASO trial updates

• Real-world evidence from ALS registries (PRO-ACT, TRICALS)

Meet-the-Expert Sessions

• Interpreting genetic test results for patients and families

• Managing cognitive and behavioral changes in ALS/FTD

• Respiratory care decisions and timing of interventions

Hands-On Workshops

• ALS functional assessment scoring (ALSFRS-R) standardization

• Non-invasive ventilation setup and troubleshooting

• Clinical trial outcome measure training

Cognitive and Behavioral Changes

ALS-FTD overlap is increasingly recognized:

• Frontotemporal dementia co-occurs in 10-15% of ALS patients

• Behavioral variant FTD (bvFTD) features: apathy, disinhibition, loss of empathy

• Language variants: non-fluent/agrammatic variant

• Screening tools: Edinburgh Cognitive and Behavioral ALS Screen (ECAS)

• Impact on research participation and treatment decisions

See Also

• Amyotrophic Lateral Sclerosis

• ALS with Frontotemporal Dementia

• C9orf72 Gene

• SOD1 Gene

• TDP-43 Protein

• AAN 2026 — Main conference page

• AAN 2026 Alzheimer’s Disease

• AAN 2026 Parkinson’s Disease

• AAN 2026 Dementia

• AAN 2026 Multiple Sclerosis

• Motor Neuron Disease