Purpose <p>To investigate the relationships among CSF proteomic pathway alterations, dopamine transporter single-photon emission computed tomography (DAT-SPECT)-derived dopamine transporter uptake measures, and cognitive vulnerability, longitudinal cognitive decline, and incident mild cognitive impairment (MCI) in early PD.</p> Methods <p>We analyzed data from the Parkinson’s Progression Markers Initiative, integrating CSF proteomics, DAT uptake measures, and longitudinal cognitive assessments. Cross-sectional analyses included 318 PD patients and 152 healthy controls with baseline clinical, DAT uptake, and CSF proteomic data. Linear mixed-effects models were used to evaluate 0-5-year cognitive trajectories in 306 PD patients, and Kaplan-Meier and Cox analyses assessed incident MCI in 255 cognitively normal PD patients at baseline.</p> Results <p>PD patients showed widespread reductions in DAT uptake across the putamen, caudate, and striatum. A total of 233 CSF proteins were differentially expressed in PD, with enrichment in neuronal development, synaptic signaling, axon guidance, Wnt signaling, glutamatergic synapse, and complement/coagulation pathways. Within PD, neural CSF pathway scores were associated with bilateral caudate DAT uptake and HVLT discrimination performance. Lower baseline bilateral caudate and striatal DAT uptake predicted less favorable longitudinal cognitive trajectories across multiple domains, while CSF pathway scores were associated with domain-specific cognitive changes. In survival analyses, low baseline bilateral caudate DAT uptake was associated with increased risk of incident MCI.</p> Conclusions <p>These findings suggest that caudate dopaminergic dysfunction may serve as a clinically relevant imaging marker of cognitive vulnerability in early PD, whereas CSF proteomic pathway alterations provide molecular context for synaptic-axonal and immune-coagulation changes associated with cognitive vulnerability and selected cognitive trajectories.</p>