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 PD AD and PD noAD according to the ATN PD 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, PD AD 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. PD AD 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.