Objective: This study focuses on mixed pathology of α-synucleinopathy and Alzheimer’s disease(AD), analyzing the relationships among biomarkers, genetic factors, and cognitive function in order to stratify dementia risk and develop biomarkers for improved disease classification.

Background: Parkinson disease(PD) is often associated with Alzheimer’s-related pathologies, such as amyloid-β(Aβ) and tau. Therefore, to predict dementia progression, it is essential to analyze coexisting Alzheimer’s with α-synuclein pathology. This study aims to stratify patients with PD based on clinical features and several disease-associated biomarkers by analyzing the relationship between biomarkers, genes and amyloid PET.

Method: In this study, 13 control cases and 49 patients with clinically diagnosed with RBD (REM Sleep Behavior Disorder) (n=10), PD (n=13), PD-MCI (PD-Mild Cognitive Impairment)(n=13), and PDD/DLB (PD with Dementia)(n=10) were enrolled and each underwent testing for amyloid PET, pTau217/Aβ42, NFL, GFAP and ApoE gene using blood tests were measured.

Results: Aβ1-40/1-42 and pTau217/Aβ1-42 showed a significant increase in amyloid PET positive group compared to the negative group. Aβ1-40/1-42 and pTau217 showed a significant increase in patients with APOE ε4 compared to those with ε3. These suggest that amyloid deposition in the brain is reflected in the plasma and APOEε4 is a risk factor for amyloid deposition.In addition, a comparison of biomarkers among the five groups showed a significant increase in ptau217 and pTau217/Aβ42 in PDD/DLB compared to RBD and PD. This indicates that amyloid deposits in the brain are also reflected in plasma. Furthermore, NFL levels were significantly higher in PD-MCI and PDD/DLB patients than in controls, GFAP was increased in the RBD, PD, PD-MCI, and PDD/DLB groups compared to the control group. This suggests that inflammation begins in the prodromal phase, followed by neurodegeneration as cognitive decline and disease progression occur.

Conclusion: Given that pTau217 and Aβ show elevated levels in the amyloid PET-positive group, plasma biomarkers may be interchangeable in PD. Furthermore, the early increase in GFAP followed by the later elevation of NfL suggests a pathological trajectory where neuroinflammation precedes significant neurodegeneration during cognitive decline. These plasma-based markers hold great potential for early diagnosis and monitoring disease progression in clinical practice.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/risk-stratification-study-of-fluid-biomarkers-for-alpha-synucleinopathy-with-dementia/