Alzheimer's Biomarkers and Visuospatial Cognition in Parkinson's Disease: Modification by α‐Synuclein and Mediation of Age Effects

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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.

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