Sex and genotype influence the disruption of circulating NMDAR-related amino acids in patients with Parkinson’s disease

Sex and genetic factors influence the epidemiology and clinical features of Parkinson’s disease (PD), but their impact on N-methyl-D-aspartate receptor (NMDAR)-related amino acids remains unclear. We measured serum levels of these molecules by high-performance liquid chromatography (HPLC) in a well-characterized cohort of PD patients (n = 245) and healthy controls (HCs, n = 203), stratified by sex and disease subtype (idiopathic, n = 121; genetic, n = 124). The genetic subgroup included carriers of pathogenic variants in LRRK2, TMEM175, PARK2, PINK1, PARK7, and GBA1. We identified marked sex-dependent differences in amino acid profiles, confirmed by linear models with interaction terms. Idiopathic male patients showed reductions in serum levels of L-glutamate, L-glutamine, L-aspartate, D-serine, L-serine, glycine, and L-asparagine compared with HCs, whereas genetic PD males displayed more limited changes. Female patients showed minimal or no significant alterations regardless of subtype. Within the PD cohort, idiopathic males exhibited lower levels of L-glutamate, L-aspartate, glycine, D-serine, and L-serine than genetic PD males, while no differences emerged between female subgroups. These findings reveal a previously unrecognized sex- and genotype-dependent regulation of NMDAR-related amino acid homeostasis in PD, highlighting the importance of biological stratification for biomarker discovery and for developing targeted, personalized therapeutic strategies.