OBJECTIVE: Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) share clinical, pathological, and genetic risk factors, including GBA1 and APOEε4 mutations. Biomarkers associated with the pathways of these mutations, such as glucocerebrosidase enzyme (GCase) activity and amyloid-beta 42 (Aβ42) levels, may hold potential as predictive indicators, providing valuable insights into the likelihood of cognitive decline within these diagnoses. Our objective was to determine their association with cognitive decline in DLB and PD. METHODS: A total of 121 DLB patients from the European-DLB Consortium and 117 PD patients from the Norwegian ParkWest Study were included in this study. The four most commonly associated variants of GBA1 mutations (E326K, T369M, N370S, L444P), APOEε4 status, and cerebrospinal fluid (CSF) Aβ42 levels and GCase activity were assessed, as well as global cognition using the Mini-Mental State Examination. Linear mixed-effects regression models were used to evaluate the association of CSF biomarkers with cognitive decline in each diagnostic group, adjusted for age, sex, education, and genetic mutation profile. RESULTS: Low CSF Aβ42 levels were associated with accelerated cognitive decline in DLB, whereas reduced CSF GCase activity predicted faster cognitive decline in PD. These associations were independent of GBA1 gene mutations or APOEε4 status. INTERPRETATION: Our study provides important evidence on the relationship between brain Aβ deposition and GCase activity in the Lewy body disease spectrum independent of their genetic mutation profile. This information could be relevant for designing future clinical trials targeting these pathways.

Ace Alzheimer Center Barcelona Universitat Internacional de Catalunya Barcelona Spain

Centre for Age Related Medicine Stavanger University Hospital Stavanger Norway

Centre for Movement Disorders Stavanger University Hospital Stavanger Norway

CIBERNED Center for Networked Biomedical Research On Neurodegenerative Diseases National Institute of Health Carlos 3 Madrid Spain

Departement of Neurology Stavanger University Hospital Stavanger Norway

Department of Chemistry Bioscience and Environmental Engineering University of Stavanger Stavanger Norway

Department of Neurology County Clinic Hospital Faculty of Medicine Transilvania University Brasov Romania

Department of Neurology Haukeland University Hospital Bergen Norway

Department of Neurology Medical University of Lublin Lublin Poland

Department of Neurology Memory Clinic Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Department of Psychological Medicine Institute of Psychiatry Psychology and Neuroscience King's College London London UK

Department of Quality and Health Technology Faculty of Health Sciences University of Stavanger Stavanger Norway

Neurology Center Assistance Publique Hôpitaux de Paris Lariboisière Fernand Widal Hospital INSERMU1144 Université de Paris Paris France

Sant Pau Memory Unit Department of Neurology IIB Sant Pau Hospital de Sant Pau Universitat Autònoma de Barcelona Barcelona Spain

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