Objective: To investigate associations between plasma biomarkers of Alzheimer’s disease (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 Parkinson’s disease (PD) cognitive spectrum, compared with dementia-free older adults (age ≥ 65 years).

Background: AD co-pathology may contribute to cognitive decline and faster progression in PD.[1,2] Although blood-based biomarkers enable biological staging along the AD continuum, their contribution  in the clinical–biological characterization of PD phenotypes remains unclear.[3]

Method: Fifty-eight PD patients (PD-NC, n=21; PD-MCI, n=29; PDD, n=8) and 76 older adults underwent brain MRI, a II-level neuropsychological/behavioral 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. [4,5]

Results: AD-related markers (p-tau217 and Aβ42/40) demonstrated stronger and distinct associations with neurostructural and clinical/cognitive measures, outperforming non-specific biomarkers (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 with higher NfL.

Conclusion: Plasma p-tau217 and Aβ42/40 reflect neurostructural and cognitive impairment in PD and older adults, supporting plasma biomarkers—particularly p-tau217—as cost-effective screening tools for AD co-pathology in PD, given the relationship with MRI-derived AD signature and poorer cognitive performance.

References: 1. Baik K, Kim HR, Park M, et al. Effect of Amyloid on Cognitive Performance in Parkinson’s Disease and Dementia with Lewy Bodies. Movement Disorders 2023;38(2):278–285. https://doi.org/10.1002/mds.29295
2. Smith C, Malek N, Grosset K, et al. Neuropathology of dementia in patients with Parkinson’s disease: a systematic review of autopsy studies. J Neurol Neurosurg Psychiatry 2019;90(11):1234–1243. https://doi.org/10.1136/jnnp-2019-321111
3. Musso G, Fiorenzato E, Misenti V, et al. Detecting amyloid and tau pathology in Parkinson’s disease, 4R-tauopathies and control subjects with plasma pTau217. Front Neurol;16. https://doi.org/10.3389/fneur.2025.1638852
4. Orellana C, Ferreira D, Muehlboeck J-S, et al. Measuring Global Brain Atrophy with the Brain Volume/Cerebrospinal Fluid Index: Normative Values, Cut-Offs and Clinical Associations. Neurodegener Dis 2016;16(1–2):77–86. https://doi.org/10.1159/000442443
5. Shiino A, Shirakashi Y, Ishida M, Tanigaki K. Machine learning of brain structural biomarkers for Alzheimer’s disease (AD) diagnosis, prediction of disease progression, and amyloid beta deposition in the Japanese population. Alzheimers Dement (Amst) 2021;13(1):e12246. https://doi.org/10.1002/dad2.12246

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MDS Abstracts - https://www.mdsabstracts.org/abstract/distinct-neurostructural-cognitive-and-neuropsychiatric-associations-of-plasma-p-tau217-and-a%ce%b242-40-in-parkinsons-disease-and-aging-cohorts/