Dopamine replacement therapy forms the cornerstone of Parkinson’s disease (PD) management; however, patient responses, drug tolerability, and safety outcomes vary widely, largely due to genetic variations affecting drug metabolism and action. Despite this, the potential of multigenetic pharmacogenomics-guided therapy (MPGT) to optimize treatment in PD has been insufficiently explored. This prospective cohort study aimed to investigate whether MPGT could improve motor function in PD patients. We followed 28 PD patients over four weeks. Among them, 22 underwent comprehensive pharmacogenomic testing, with 13 receiving treatment tailored according to their genetic profiles (MPGT group), while 15 received conventional therapy (TAU group). Baseline characteristics, changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) III total and sub-scores, and associations between specific single nucleotide polymorphisms (SNPs) and treatment outcomes were assessed using generalized linear models. At the end of the 4-week period, patients in the MPGT group showed significantly greater improvements in UPDRS III total scores (p < 0.05) and limb sub-scores (p < 0.01) than those in the TAU group. These differences remained significant after accounting for increases in levodopa equivalent daily dose (p = 0.011 and p = 0.002, respectively) and piribedil use (p = 0.006 and p = 0.004, respectively). Additionally, carriers of major homozygous alleles for rs4984241 (AA vs. AG+GG, p = 0.003), rs4680 (GG vs. GA+AA, p = 0.013), rs1076560/rs2283265 (CC vs. AC+AA, p = 0.039), and rs622342 (AA vs. AC, p = 0.043) experienced greater improvements in total UPDRS III, postural instability and gait difficulty (PIGD), rigidity, and tremor scores, respectively, compared to individuals carrying at least one minor allele. MPGT demonstrates considerable potential for personalizing PD treatment and enhancing motor outcomes, with certain SNPs appearing to influence response to long-term anti-parkinsonian therapy. Larger, well-designed studies are warranted to confirm these results and support broader clinical application.
