Objective: To identify a proteomic profile associated with the future development of dementia in recently diagnosed Parkinson’s disease (PD) patients.

Background: Dementia is a common non-motor manifestation of PD that predicts poor long-term prognosis. However, early identification of at-risk individuals remains a challenge.

Method: We used the NULISAseq^TM CSF Disease Panel 120 to quantify baseline serum proteins from 727 individuals with PD from the PROBAND study. Each participant had on average 3.4 (SD ± 1.3) cognitive assessments over a mean period of 3.9 (SD ± 2.1) years after study enrolment. Dementia was defined based on the Movement Disorders Society (MDS) Task Force recommendations. Cox proportional hazards models adjusted for sex, age at serum sampling, disease duration and batch were used to identify proteins associated with dementia-free survival. P-values were adjusted using the Benjamini-Hochberg (BH) method.

Results: 10.7% of individuals developed dementia after a median (IQR) of 3.1 (0.5-5.7) years of study follow up. Increased baseline levels of phosphorylated tau proteins (pTau181, pTau231 and pTau217), which are established Alzheimer’s disease (AD) biomarkers, were associated with the subsequent development of dementia, likely reflecting the frequent co-occurrence of AD pathology in PD dementia. In addition, reduced serum levels of NPTXR early after diagnosis of PD were strongly associated with future dementia risk (Hazard Ratio [95% Confidence Interval] per NULISA Protein Quantification (NPQ) unit change = 2.09 [1.34-3.27], adjusted P = 0.029), a finding that was replicated in the independent PPMI cohort and was independent of APOE4 carrier status.

Conclusion: We identified several proteins associated with time-to-dementia in PD, some of which could be a marker of underlying AD-type co-pathology. Consistently, adjusting for APOE4 status, which has been shown to be associated with amyloid-β plaques and neurofibrillary tangles (NFTs), abolished some of the protein signals. However, reduced levels of NPTXR were associated with conversion to dementia independently of APOE4 status. Together with replication in an independent cohort, this suggests that NPTXR, a marker of synaptic integrity, is a robust candidate biomarker to identify PD patients at risk of dementia several years before cognitive impairment develops, and that synaptic dysfunction is an early event in PD cases who will go on to develop dementia.

References: A version of this abstract has been presented at the AAIC Neuroscience Next meeting on the 26th February 2026.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/predicting-dementia-in-parkinsons-disease-using-blood-based-proteomics/