Objective: To analyze whether and how cerebrospinal fluid (CSF) amyloid-related markers relate to the longitudinal cognitive profile in PD-GBA1.

Background: Cognitive decline in Parkinson’s disease (PD) varies with factors including amyloid and tau pathology and genotype, such as pathogenic mutations of the Glucocerebrosidase gene (GBA1)(1). GBA1 in PD (PD-GBA1) impairs lysosomal-mediated alpha-synuclein degradation and is linked to a greater risk of cognitive impairment compared to GBA1-wildtype carriers (PD-GBA1_WT)(2). Although some findings on the role of CSF markers for global cognition in PD-GBA1 have been reported(3,4), evidence of their link to cognitive domains is limited.

Method: Cognitive decline in Parkinson’s disease (PD) varies with factors including amyloid and tau pathology and genotype, such as pathogenic mutations of the Glucocerebrosidase gene (GBA1)(1). GBA1 in PD (PD-GBA1) impairs lysosomal-mediated alpha-synuclein degradation and is linked to a greater risk of cognitive impairment compared to GBA1-wildtype carriers (PD-GBA1_WT)(2). Although some findings on the role of CSF markers for global cognition in PD-GBA1 have been reported(3,4), evidence of their link to cognitive domains is limited.

Results: Abnormal Aβ_1-42 and [p/t]-tau/Aβ_1-42 levels occurred earlier in PD-GBA1 than in PD-GBA1_WT. T-tau also increased more over time in PD-GBA, primarily due to pathogenic GBA1 variants. Overall, the occurrence of both abnormal Aβ_1-42 and p-tau levels was rare. Lower Aβ_1-42 and higher [p/t]-tau/Aβ_1-42 levels were linked to worse cognitive trajectories in both groups, affecting more cognitive domains in PD-GBA1_WT. Bootstrapping showed more pronounced Aß_1-42-related decline in global cognition and memory in PD-GBA1 than in PD-GBA1_WT. Likewise, p-tau/Aβ_1-42-related decline in memory and visuospatial skills was more pronounced in PD-GBA1 than in PD-GBA1_WT. Abnormal Aβ_1-42 and [p/t]-tau/Aβ_1-42 were linked to greater cognitive decline risks in groups. Bootstrapping showed higher mnestic MCI risk in PD-GBA1 for abnormal [p/t]-tau/Aβ_1-42.

Conclusion: CSF markers, particularly (p/t)-tau/Aβ_1-42, may also help to identify PD-GBA1 patients at risk for cognitive decline, specifically regarding amnestic impairment. Future studies examining the interplay among amyloid, tau, and α-synuclein pathologies could provide insights into this enhanced vulnerability.

References: 1. Aarsland D, Batzu L, Halliday GM, Geurtsen GJ, Ballard C, Ray Chaudhuri K, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primer. 2021 Jul 1;7(1):1. doi:10.1038/s41572-021-00280-3
2. Höglinger G, Schulte C, Jost WH, Storch A, Woitalla D, Krüger R, et al. GBA-associated PD: chances and obstacles for targeted treatment strategies. J Neural Transm. 2022 Sep;129(9):9. doi:10.1007/s00702-022-02511-7
3. Lerche S, Schulte C, Srulijes K, Pilotto A, Rattay TW, Hauser AK, et al. Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles. Mov Disord. 2017;32(12):1780–3. doi:10.1002/mds.27199
4. Botta R, Locascio JJ, Ye R, Goodheart AE, Gomperts SN. APOE, Aβ42, and tau differentially impact cognitive decline in Sporadic, GBA1 and LRRK2 Parkinson’s disease. Npj Park Dis. 2026 Feb 23. doi:10.1038/s41531-026-01290-2 [advance online publication]

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebrospinal-fluid-markers-are-associated-with-cognitive-decline-in-gba1-associated-parkinsons-disease/