Objective: To investigate the prevalence and clinical relevance of AD co-pathology, assessed through fluid biomarkers, in patients with clinical 4R-tauopathies.

Background: 4R-tauopathies are neurodegenerative diseases characterized by the accumulation of four-repeat tau isoforms in neurons and glial cells[1]. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are the most common ones. The latest PSP diagnostic criteria[2] introduced the category of “probable 4R-tauopathies” to encompass phenotypes likely reflecting either PSP or CBD pathology.

Neuropathological evidence shows that CBD and PSP are rarely pure, frequently exhibiting co-pathologies, most commonly Alzheimer’s disease (AD)[3]. Large neuropathological studies further support that specific fluid biomarkers (plasma pTau217 and CSF Aβ42/Aβ40 ratio) are specific for AD co-pathology in frontotemporal lobar degeneration, including CBD and PSP[4], [5].

Method: Sixty-two patients with probable PSP or probable 4R-tauopathy, confirmed after ≥6 months follow-up, were included, underwent neurological and level II neuropsychological evaluation, brain MRI, and blood sampling; forty also underwent lumbar puncture. Plasma pTau217 (Lumipulse G1200), plasma NfL, GFAP, and pTau181 (Simoa), and CSF Aβ42, Aβ40, total tau, and pTau181 (ELISA) were measured.

Results: Sixteen patients (25.8%) had pTau217 levels above the threshold of 0.22 ng/L, previously validated in a multicentric study [6] and in our center [7]. pTau217 inversely correlated with CSF Aβ42/Aβ40 ratio. After adjustment for age, sex, and education, higher pTau217 concentrations were associated with lower MoCA Memory Index Score (MoCA-MIS; p=0.017) and higher Parkinson’s Disease–Cognitive Functional Rating Scale (PD-CFRS) scores (p<0.001), whereas associations with MoCA total score and composite language Z-scores were not significant; lower CSF Aβ42/Aβ40 ratio was associated with worse MoCA, MoCA-MIS, composite Z-scores in language and visuospatial domains, and higher PD-CFRS scores.

At MRI, after age- and sex-adjustment, the Aβ42/40 ratio correlated with bilateral thalamic and hippocampal atrophy, and logarithm-scaled pTau217 levels inversely correlated with temporo-parietal junction cortical volume (p<0.001 for all reported correlations).

Conclusion: In this cohort, fluid AD-related biomarkers were correlated with worse global cognition and memory abilities, functional dependance and distinct MRI atrophy patterns.

References: [1] M. Stamelou, G. Respondek, N. Giagkou, J. L. Whitwell, G. G. Kovacs, and G. U. Höglinger, “Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies,” Nat. Rev. Neurol., vol. 17, no. 10, pp. 601–620, Oct. 2021, doi: 10.1038/s41582-021-00541-5.
[2] G. U. Höglinger et al., “Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria,” Movement Disorders, vol. 32, no. 6, pp. 853–864, Jun. 2017, doi: 10.1002/mds.26987.
[3] J. L. Robinson et al., “Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated,” Brain, vol. 141, no. 7, pp. 2181–2193, Jul. 2018, doi: 10.1093/brain/awy146.
[4] L. VandeVrede et al., “Detection of Alzheimer Neuropathology in Alzheimer and Non-Alzheimer Clinical Syndromes With Blood-Based Biomarkers,” JAMA Neurol., vol. 82, no. 4, p. 344, Apr. 2025, doi: 10.1001/jamaneurol.2024.5017.
[5] N. Mattsson-Carlgren et al., “Cerebrospinal Fluid Biomarkers in Autopsy-Confirmed Alzheimer Disease and Frontotemporal Lobar Degeneration,” Neurology, vol. 98, no. 11, Mar. 2022, doi: 10.1212/WNL.0000000000200040.
[6] S. Palmqvist et al., “Plasma phospho-tau217 for Alzheimer’s disease diagnosis in primary and secondary care using a fully automated platform,” Nat. Med., vol. 31, no. 6, pp. 2036–2043, Jun. 2025, doi: 10.1038/s41591-025-03622-w.
[7] G. Musso et al., “Diagnostic performances and cut-off verification of blood pTau 217 on the Lumipulse platform for amyloid deposition in Alzheimer’s disease,” Clinical Chemistry and Laboratory Medicine (CCLM), vol. 63, no. 4, pp. e113–e116, Mar. 2025, doi: 10.1515/cclm-2024-1091.

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