Alzheimer's Biomarkers and Visuospatial Cognition in Parkinson's Disease: Modification by α-Synuclein and Mediation...

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.

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.

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.

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.

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.