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Lookup NU author(s): Dr David Ledingham, Dr Sahana Sathyanarayana, Charlotte StewartORCiD, Robyn Iredale, Victoria Foster, Debra Galley, Dr Meher LadORCiD, Professor Mark BakerORCiD, Professor Nicola PaveseORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Background: Visuospatial deficits in Parkinson's disease (PD) often precede dementia and complicate daily functioning. Alzheimer's disease (AD) pathology and α-synuclein aggregation frequently co-occur in PD, but their combined impact on cognition is unclear. Objectives: To examine whether AD biomarker burden relates to visuospatial performance in PD, whether this effect differs by α-synuclein status, and whether AD biomarkers mediate age-related decline. Methods: We analyzed 416 participants from the Parkinson's Progression Markers Initiative. AD biomarker burden was indexed by the cerebrospinal fluid pTau181/Aβ42 ratio; α-synuclein aggregation was assessed using seed amplification assay. Models adjusted for age, sex, education, and motor severity. Sensitivity analyses included genetic stratification and subgroup exclusion. Results: Higher AD biomarker burden was associated with poorer visuospatial performance and delayed recall. In participants with concurrent biomarker data (n = 246), AD burden interacted with α-synuclein status to predict worse visuospatial outcomes, with the greatest impairment observed in individual's positive for both biomarkers. Mediation analysis indicated that AD biomarker burden accounts for approximately 10–14% of the age effect on visuospatial performance. Conclusions: AD and α-synuclein biomarkers show associations consistent with synergistic effects on visuospatial cognition in PD. These findings are exploratory and require replication in pre-specified independent cohorts. However, if validated, testing both biomarkers could help identify individuals at higher risk of early visuospatial decline and inform hypothesis-driven stratification in future clinical trials.
Author(s): Ledingham D, Sathyanarayana S, Stewart CB, Iredale R, Foster V, Galley D, Lad M, Baker MR, Pavese N
Publication type: Article
Publication status: Published
Journal: Movement Disorders Clinical Practice
Year: 2026
Pages: epub ahead of print
Online publication date: 06/03/2026
Acceptance date: 09/02/2026
Date deposited: 09/04/2026
ISSN (print): 2330-1619
ISSN (electronic): 2330-1619
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/mdc3.70576
DOI: 10.1002/mdc3.70576
Data Access Statement: The datasets generated and/or analyzed during the current study are freely available following written request, from https://www. ppmi-info.org/access-data-specimens/download-data.
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