The research, led by a team at the University of Rome Tor Vergata together with collaborators at IRCCS Santa Lucia Foundation, IRCCS Neuromed, the Italian National Institute of Health, Sapienza University of Rome and the National Research Council of Italy, set out to answer a deceptively simple question: if Alzheimer’s co-pathology makes Parkinson’s worse, what is the biological machinery that makes it worse? The answer, published in npj Parkinson’s Disease, points not to a single molecule but to a multilayered immunometabolic signature — a coordinated shift in inflammation, cell populations and cellular energy metabolism that is visible in peripheral blood during the earliest clinical stages of disease.

Alzheimer’s co-pathology in Parkinson’s is not a fringe concern. Post-mortem and imaging studies have long shown that a substantial fraction of Parkinson’s patients also harbor amyloid plaques, tau tangles or both, and that this overlap is associated with faster cognitive decline, poorer prognosis and greater clinical complexity. But until now, the peripheral immune correlates of this malignant subtype have remained poorly characterized, particularly at early disease stages when interventions could still alter the trajectory.

To probe this, the researchers enrolled 47 patients with early-stage Parkinson’s disease and 50 age-matched healthy controls. Rather than treating Parkinson’s as a single entity, they stratified patients using the ATN framework — a classification system originally developed for Alzheimer’s disease that groups individuals according to the presence of amyloid pathology (A), tau pathology (T) and neurodegeneration or injury (N). This allowed the team to separate patients into two biologically distinct groups: those with Alzheimer’s co-pathology, labeled PD(AD), and those without, labeled PD(noAD). The comparison was designed to reveal not just whether Parkinson’s alters immunity, but whether carrying an additional Alzheimer’s burden reshapes that alteration in a qualitatively different way.

The team performed a multidimensional immunological workup on each participant, combining blood cell counts, plasma inflammatory mediators, detailed flow-cytometric profiling of circulating mononuclear cells and direct measurements of cellular energy metabolism. This was not a single-biomarker hunt. It was an attempt to map the immune system as a system — regulatory branches and effector branches, resting and activated states, mitochondrial respiration and glycolysis — and to see where the architecture buckles under disease pressure.

Across the entire Parkinson’s cohort, the changes were subtle. But when patients were separated by co-pathology, the picture sharpened dramatically. Patients in the PD(AD) group showed heightened systemic inflammation, evident both in altered blood cell counts and in elevated plasma mediators. Their circulating mononuclear cells were in a hypermetabolic state, with upregulated mitochondrial respiration and glycolysis — the two main energy pathways immune cells use to fuel activation. In parallel, the regulatory arm of innate immunity was depleted, while effector CD8 T cells and B-cell populations were expanded, with T-cell cytotoxic hyperresponsiveness. In short, the brakes were lifted and the accelerator was pressed at the same time.

This combination is biologically telling. Heightened inflammation signals that the immune system is being chronically provoked. A hypermetabolic state in mononuclear cells indicates that those cells are not merely present in greater numbers but are actively burning energy to sustain an activated phenotype. Depletion of regulatory innate cells removes a key counterweight that normally restrains runaway responses. Expansion of cytotoxic CD8 T cells and B cells, together with T-cell cytotoxic hyperresponsiveness, suggests that the effector machinery — the part of immunity designed to kill infected or abnormal cells — is primed beyond what the regulatory system can contain. Together, these shifts form a coordinated, multilayered signature rather than a scattered set of anomalies.

Notably, the researchers found no association between this immunometabolic signature and the APOE genotype, the strongest known genetic risk factor for sporadic Alzheimer’s disease. This is an important dissociation: it suggests that the malignant subtype defined by co-pathology is not simply a reflection of inherited Alzheimer’s risk but is instead associated with a distinct systemic pathogenic construct — a body-wide immune and metabolic state that accompanies, and may actively contribute to, the worse clinical course seen in these patients.

The implications reach well beyond classification. If immunometabolism constitutes a pivotal axis of biological heterogeneity in Parkinson’s disease, as the authors argue, then the signature they describe could serve as a framework for biomarker discovery — a way to identify, from a simple blood draw, which patients are carrying the co-pathology burden that predicts faster decline. It also suggests a framework for intervention: if the hyperinflammatory, hypermetabolic state is a driver rather than a byproduct, then therapies aimed at restoring immune regulation, tempering effector cytotoxicity or normalizing cellular energy metabolism could be tailored specifically to this subtype. The study was funded by the Italian Ministry of University and Research through a PRIN 2022 grant and by the European Union’s NextGenerationEU initiative through the Italian Ministry of Health.

For a field that has long treated Parkinson’s as a movement disorder with cognitive complications, the study reframes the disease as a condition in which peripheral immunity and cellular metabolism are not bystanders but active participants in shaping clinical outcome. It suggests that the blood of an early-stage Parkinson’s patient already carries information about the biological subtype they harbor — and that decoding that information could change how the disease is monitored, subtyped and treated long before motor symptoms define the clinical picture.

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

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

Article References: Mascioli, D., Nesci, V., Veltri, F., Bissacco, J., Di Liberto, E., Simonetta, C., Mancini, M., Buttarazzi, V., Conti, M., Rosina, M., Maftei, D., Sancesario, G. M., Carrera, G., Ceci, V., Saracini, S., Stefani, A., Pierantozzi, M., Centonze, D., Valle, C., … Schirinzi, T. (2026). A distinct immunometabolic signature defines early-stage Parkinson’s disease with Alzheimer’s disease co-pathology. npj Parkinson's Disease. https://doi.org/10.1038/s41531-026-01594-3

Image Credits: AI Generated

DOI: 10.1038/s41531-026-01594-3

Keywords: Parkinson's disease, Alzheimer's co-pathology, immunometabolism, biomarkers, neuroinflammation, mitochondrial respiration, ATN framework, T-cell cytotoxicity, distinct, immunometabolic, signature, defines