A distinct immunometabolic signature defines early-stage Parkinson’s disease with Alzheimer’s disease co-pathology

Alzheimer’s disease (AD) co-pathology is associated with a worse prognosis in Parkinson’s disease (PD). To elucidate the pathogenic basis of this malignant subtype, we performed a multidimensional immunological analysis of 47 patients with early-stage PD, grouped into PDAD and PDnoAD according to the ATNPD framework, and 50 healthy controls. Subtle changes observed in the whole PD population were more pronounced when patients were stratified by co-pathology.

In particular, PDAD exhibited heightened inflammation (as evidenced by blood cell counts and plasma mediators) and a hypermetabolic state of circulating mononuclear cells, with upregulated mitochondrial respiration and glycolysis; the regulatory innate cells were depleted, and the effector CD8 and B-cell populations expanded, with T-cell cytotoxic hyperresponsiveness. No associations were observed with the APOE genotype. PDAD entails a multilayered signature of peripheral immunity, suggesting a systemic pathogenic construct.

Immunometabolism constitutes a pivotal axis of biological heterogeneity in PD, providing a framework for biomarker discovery and intervention. The research leading to these results has received funding from the Italian Ministry of University and Research (MIUR) by “PRIN Bando 2022 Prot. 20222FYK9R” to TS. This study has also been supported by the European Union (NextGenerationEU) through the Italian Ministry of Health (PNRR-MCNT1-2023-12378408) to M.P. and (PNRR-MAD-2022-12376556) to NMB, V.Ch. and T.S.

The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. These authors contributed equally: Davide Mascioli, Valentina Nesci. These authors jointly supervised this work: Alberto Ferri, Valerio Chiurchiù, Tommaso Schirinzi.

Unit of Neurology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy Davide Mascioli, Valentina Nesci, Federica Veltri, Jacopo Bissacco, Clara Simonetta, Maria Mancini, Veronica Buttarazzi, Matteo Conti, Alessandro Stefani, Mariangela Pierantozzi, Diego Centonze & Tommaso Schirinzi Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy Jacopo Bissacco, Diego Centonze & Tommaso Schirinzi Laboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia Foundation, Rome, Italy Eugenia Di Liberto, Giulia Carrera, Veronica Ceci, Stefano Saracini & Valerio Chiurchiù Italian National Institute of Health (ISS), Department of Neuroscience, Rome, Italy Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, Italy IRCCS Fondazione Santa Lucia, European Centre for Brain Research, Rome, Italy PhD Program in Neuroscience, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy Institute of Translational Pharmacology (IFT), National Research Council of Italy (CNR), Rome, Italy Veronica Ceci, Cristiana Valle, Alberto Ferri & Valerio Chiurchiù Laboratory of Neurochemistry, IRCCS, Santa Lucia Foundation, Rome, Italy The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

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