Synuclein Disorder‐Related Genetic Determinants of Mild Behavioural Impairment in a Pre‐Clinical Community Cohort

Background The GBA variant confers increased risk of synuclein disorders but it is unclear what impact it has in pre‐clinical groups. This study aimed to identify early psychiatric and cognitive manifestations amongst pre‐clinical GBA carriers in a community cohort. Method This study used data from the PROTECT‐UK cohort to compare 388 GBA carriers (N370S, E326K and T369M) without Parkinson's disease to age‐matched controls. Neuropsychiatric symptoms (NPS) were measured with the Mild Behaviour Impairment Checklist, and cognition was measured using computerised neuropsychology. Results Results: GBA carriers over 70 had significantly increased NPS compared with controls ( z = 2.13, p = 0.03). There was no difference between carriers and non‐carriers in younger individuals but a sub‐group comparison in the overall cohort showed that NPS were more severe in quartile four (Q4) of carriers compared to Q4 of controls ( z = 2.39, p = 0.017), indicating an increase in NPS in this sub‐group across a broader age range. No differences in cognition were seen. Discussion These findings suggest that NPS may be an early clinical manifestation of emerging synucleinopathy amongst individuals prior to diagnosis.