Unraveling the Relationship between Plasma pTau217 and Cognitive Function in Parkinson’s Disease

Introduction: In recent years, blood-based biomarkers, in particular plasma phospho-tau 217 (pTau217), have emerged as a reliable biomarker of Alzheimer’s disease (AD) pathology, reflecting both amyloid and tau burden. However, the relationship between AD-related pathology and cognition in synucleinopathies, particularly in Parkinson’s disease (PD), remains poorly understood. The present study aims to investigate the relationship between higher plasma pTau217 concentrations and cognitive performance in PD. Specifically, the goal is to characterize AD-related pathology in PD patients across the entire cognitive spectrum, in comparison with a control group including cognitively unimpaired (CU) and mild cognitive impairment (MCI) individuals. Methods: Seventeen cognitively unimpaired PD patients (PD-CU), 27 PD patients with mild cognitive impairment (PD-MCI) and 9 PD patients with dementia (PDD), together with one patient with dementia with Lewy bodies (DLB) grouped under PDD/DLB, were recruited. The control group (CG) included 51 cognitively unimpaired (CU) and 29 MCI individuals. Plasma pTau217 was measured using the fully automated Lumipulse platform and the presence of AD-related pathology was defined according to a previously validated cutoff based on amyloid-beta position emission tomography (Aβ-PET). All participants underwent cognitive assessment, including global cognitive screening and domain-specific neuropsychological tests. Functional and clinical-behavioral information was also collected. Results: AD co-pathology was more prevalent in individuals with greater cognitive impairment: 60% of PDD patients, 26% of those with PD-MCI, and none of the PD-CU group were pTau217-positive. Among controls, 45% of MCI individuals were positive, whereas only 10% of CU individuals showed pTau217 positivity despite preserved cognition. In the PD group, pTau217 positivity was associated with poorer performance on global cognitive screening, as assessed by the Montreal Cognitive Assessment (MoCA) (pFDR=0.030), and Mini-Mental State Examination (pFDR=0.030), but not on the MoCA Memory Index Score (MoCA-MIS). At the cognitive-domain level, executive functions (pFDR=0.024), attention/working memory (pFDR=0.046) and language (pFDR=0.046) were the most affected. The neuropsychological tests showing the strongest discrimination by pTau217 status included the Symbol Digit Modalities Test, Clock Drawing test, Stroop test, and Semantic Fluency. Notably pTau217+ PD patients showed shorter disease duration but greater motor severity, and presented higher functional impairment as well as more depressive, anxious and impulsive symptoms. Discussion: Plasma pTau217 positivity was associated with worse cognitive performance in both PD patients and controls, though with distinct profiles. In PD, impairments were most pronounced in executive, attentional and language domains, while in controls pTau217 positivity was linked to a broader “Alzheimer-like” profile with prominent memory, language and social cognition deficits. pTau217+ individuals were more prevalent in the PDD (60%), and the MCI group (45%), followed by a slightly lower prevalence in the PD-MCI group (26%). Noteworthy, pTau217 positivity in PD was linked to a shorter disease duration and greater motor severity, suggesting that the presence of a concomitant AD-pathology may hasten PD progression. Furthermore, pTau217 positivity in PD was linked to greater functional impairment and more depressive, anxious and impulsive symptoms. Together, these findings support the role of pTau217 as a marker of AD co-pathology that interacts with PD-related pathology, accelerating decline in domains already vulnerable to synucleinopathy.