Anti-IgLON5 disease is a neurological disorder that associates with antibodies against IgLON5, a neuronal cell-adhesion protein of unknown function. Most patients develop a combination of prominent sleep alterations (non-rapid eye movement (NREM) and REM parasomnias with obstructive sleep apnoeas), bulbar dysfunction (dysarthria, dysphagia, vocal cord palsy, or episodes of respiratory failure), and gait instability. Initial autopsy studies showed deposits of phosphorylated tau protein predominantly in neurons of the tegmentum of the brainstem, suggesting a primary neurodegenerative disease. However, findings in subsequent studies have provided increasing support to an immune-mediated pathogenesis. First, there is a strong association with the human leukocyte antigen (HLA) haplotype DRB1*10:01–DQB1*05:01 which is present in ~60% of patients (compared to 2% in the normal population); second, recent autopsy studies showed absence of abnormal deposits of tau; and third, in live neurons in culture, IgLON5 antibodies cause an irreversible loss of surface IgLON5 clusters and changes in the cytoskeleton such as dystrophic neurites and axonal swellings. Taken together, these studies suggest that an antibody-mediated disruption of IgLON5 function leads to neurofilament and cytoskeletal alterations that can potentially result in tau accumulation.