About 13% of clinically diagnosed Parkinson's patients were negative on CSF α‑synuclein seed amplification assay and showed distinct clinical features suggesting a subgroup with low or absent Lewy body pathology.

This supports CSF α‑syn SAA as a stratification biomarker for trials and implies α‑synuclein–targeted therapies may not be appropriate for all PD patients, improving patient selection and trial design.

We investigated the basis and clinical correlates of a negative cerebrospinal fluid (CSF) alpha-synuclein (α-syn) seed amplification assay result in patients with a clinical diagnosis of sporadic or GBA1-associated PD formulated by movement disorder specialists. Out of 473 participants with a confirmed PD diagnosis at the last follow-up, 62 (13.1%) were α-syn negative. Among them, 3 out of 15 with available longitudinal CSF samples converted to α-syn positive. Alpha-syn negative participants had more severe axial motor impairment, lower odds of hyposmia, REM sleep behaviour disorder and constipation. There were no differences in motor and cognitive progression between groups. CSF neurofilament light chain values were not associated with α-syn status. Besides possible misdiagnosis, the results indicate that α-syn negative PD comprises a distinct patient subgroup, possibly associated with a low burden or absence of Lewy body pathology. The results support the use of CSF α-syn SAA in PD patient stratification.