Distinct neurostructural, cognitive, and neuropsychiatric associations of plasma p-tau217, and Aβ42/40 in Parkinson’s disease and aging cohorts

Objective Alzheimer’s disease (AD) co-pathology may contribute to cognitive decline and faster progression in Parkinson’s disease (PD). Although blood-based biomarkers enable biological staging along the AD continuum, their contribution in the clinical-biological characterization of PD phenotypes remains unclear. We investigated associations between plasma biomarkers of AD-pathology [phosphorylated-tau-217(p-tau217), amyloid-beta-42/40 (Aβ42/40)], neurodegeneration [neurofilament light chain (NfL)], and neuroinflammation [glial fibrillary acidic protein (GFAP)] with MRI-derived neurostructural indices, cognition, functional independence, and neuropsychiatric symptoms across the PD cognitive spectrum, compared with dementia-free older adults. Methods Fifty-eight PD patients and 76 older adults underwent brain MRI, neuropsychological assessment, and plasma biomarker quantification. Multiple linear regressions examined associations between plasma biomarkers and MRI-derived measures (global atrophy, hippocampal volume, AD-specific signature) and clinical measures. Results AD-pathology markers (p-tau217 and Aβ42/40) showed stronger associations with neurostructural and clinical/cognitive measures than NfL and GFAP. In both cohorts, higher p-tau217 was associated with AD-like MRI alterations and worse global cognition. Further, in PD, p-tau217 reflected memory and executive dysfunctions, while lower Aβ42/40 was associated with reduced functional independence, visuospatial, and socio-cognitive deficits. In older adults, elevated p-tau217 was linked to subjective cognitive decline, language/memory deficits; lower Aβ42/40 to global atrophy, attention, visuospatial and memory deficits. Neuropsychiatric symptoms in PD (depressive mood, anxiety, apathy) were primarily associated with AD-pathology markers, whereas depressive symptoms in older adults were linked to higher NfL. Conclusion Plasma p-tau217 and Aβ42/40 were associated with neurostructural and cognitive impairment in PD and older adults, supporting the potential utility of AD-related plasma biomarkers—particularly p-tau217—for the clinical-biological characterization of cognitive decline in PD.