Can we predict neurodegeneration? p-tau 217 as a biormaker of cognitive impairment: a comparison between controls and Parkinsonians

Introduction: Plasma phospho-tau 217 (p-tau217) is a biomarker for Alzheimer’s disease (AD) pathology, reflecting tau and Aβ burden. However, p-tau217 plays a significant role also in the Parkinson’ s disease (PD) pathology, even if it is not completely understood. In this study, we measured plasma p-tau217 levels across cognitively unimpaired (CU) and the cognitive spectrum of Lewy Body Disorders (LBD): Parkinson’s disease with normal cognition (PD-NC), Parkinson’s disease with mild cognitive impairment (PD-MCI), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB). Aim of the study: In this study, we aim to measure plasma p-tau217 across LBD with various degrees of cognitive dysfunctions - ranging from PD-NC, PD-MCI, PDD and DLB - comparing these results relative to CU and MCI individuals. Further, we adopted a p-tau217 cut-off of 0.22 ng/L previously validated against Aβ-PET imaging, as a proxy of AD pathology to determine its presence. Material and methods: Participants included a total of 265 individuals. Specifically, 72 CU and 128 patients: 122 PD with various degree of cognitive dysfunction (22 PD-NC, 66 PD-MCI, 40 PDD/DLB) and 6 with a diagnosis of DLB. p-tau217 was tested in K-2 ethylenediaminetetraacetic acid plasma samples with a research-use-only Lumipulse G1200 assay. Samples were aliquoted in polypropylene tubes and kept frozen at −80°C and handled as previously reported before analyses. Results: Plasma p-tau217 concentrations significantly differed across groups. Specifically, CU individuals showed lower p-tau217 levels than MCI [t(259)= -7.36; p < 0.001], PD-MCI [t(259)= -2.62; p= 0.04], PDD [t(259)= -3.78; p < 0.001]; whereas MCI had higher levels than PD-NC [t(259)= 1.07; p < 0.001]. PD-NC showed lower levels than PD-MCI[t(259)= - 2.90; p= 0.02] and PDD [t(259)= -3.89; p < 0.001]. Discussion: Our main finding is that plasma p-tau217 concentrations, were significantly more elevated in PD groups with higher cognitive dysfunction (PD-MCI, PDD/DLB), and in individuals with MCI, compared to PD-NC and CU. As expected, the highest percentage of p-tau217 positivity was observed in the MCI group, with a percentage of 58%. By contrast, only 13 % CU showed p-tau positivity. This result is not surprising but is aligned with previous evidence which interprets elevated p-tau as an early physiological response to brain Aβ plaque deposition, preceding the widespread aggregation of neurofibrillary tangles. As a consequence, our results outline the role of p-tau217 as a non-invasive, cost-effective biomarker for identifying individuals at risk of cognitive decline in older adults as well as in PD patients.