Dates: April 18-22, 2026
Location: McCormick Place, Chicago, Illinois
Track: Motor Neuron Diseases and Neuromuscular Disorders
Overview
Mermaid diagram (expand to render)
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[@meijel2023]:
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[@benatar2024]:
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[@gauthie2024]:
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[@paganoni2024]: