Persisting Transglutaminase 6 Antibodies in Neurological Gluten-Related Disorders

Gluten-related autoimmunity can cause neurological disease, although the best way to diagnose and monitor such patients is unclear. Serological testing for antibodies against transglutaminase 6 (TG6) has been proposed; however, this is not widely available in clinical practice. Using longitudinal data from patients attending a specialist neurological center with routine TG6 testing, this observational study explores how antibody history relates to brain atrophy, cognition, and quality of life.

Serological records of patients with gluten-related neurological disease were collected alongside clinical brain magnetic resonance imaging. Patients were recruited to undertake questionnaires that assessed/included chronic symptom severity, the hospital anxiety and depression scale, the SF-12, and the Biagi scale for gluten-free diet adherence. Volunteers were offered the cerebellar cognitive affective syndrome scale for cognitive testing. Primary analyses focused on patients with ≥5 years of serology (n = 462), and related TG6 history to available clinical outcomes (primary analysis range 89-104).

Patients with a previous positive immunoglobulin A (IgA) TG6 result reported greater depression, symptom severity, and poorer physical functioning. IgA TG6 antibody exposure was correlated with regional brain atrophy (age-corrected). Greater self-reported gluten-free diet adherence significantly predicted a recent negative IgA TG6 test. Subgroup analyses replicated multiple findings in patients with and without celiac disease.

TG6 testing can identify patients at risk of accelerated brain atrophy, poorer physical functioning, and worsened mental health. IgA TG6 should be used as a diagnostic and monitoring test for patients with relevant neurological presentations, while achieving negative serology with a strict gluten-free diet should be the goal. ANN NEUROL 2026;99:274-282.