Proteomic profiles in Lewy body pathology and the presence of AD co‐pathology
Bibliographic record
Abstract
Abstract Background Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are neurodegenerative disorders that often overlap with Alzheimer's disease (AD), complicating diagnosis and patient management. The role of α‐synuclein aggregation in LBD and its interplay with AD pathology remains unclear. Biomarkers like DOPA decarboxylase (DDC) have shown promise in differentiating healthy controls, PD, and AD. However, molecular mechanisms underlying disease heterogeneity in LBD require further investigation. Here we examine proteomic differences associated with α‐synuclein pathology and its clinical manifestations, including cognitive decline and parkinsonism symptoms. Method We analyzed 1,388 proteins from CSF Olink of 915 participants from the Swedish BioFINDER‐2 cohort, incorporating CSF α‐synuclein seeding amplification assays (SAA) and AD pathology biomarkers ( p ‐tau181/Aβ42). Participants were classified as cognitively unimpaired or impaired (MCI/dementia) and by the presence of parkinsonism. Associations between CSF proteins and SAA pathology, cognitive status, and parkinsonism were assessed using a single linear regression model, adjusting for age, sex, and mean protein levels. Differentially abundant proteins (DAP) across the three conditions (pFDR<0.05) were further evaluated after adjusting for AD pathology. Functional and cell‐type enrichment analyses were performed upregulated and downregulated DAPs separately across conditions. We then identified proteins included in the resulting biological and cellular processes to assess in which conditions they were abundant. Result Among 287 SAA+ participants, 110 had parkinsonism symptoms, 198 had cognitive impairment, and 51 were clinically unimpaired (Table 1). We identified 129 DAPs across all conditions: 82 remaining significant after adjusting for AD pathology (Figure 1). Most DAPs were linked to cognitive status, with minimal overlap across conditions (Figure 1B). Downregulated proteins were enriched in synaptic processes, particularly neuronal signaling, cell junction assembly, and axonogenesis (Figure 2). Notably, DDC was consistently upregulated across all conditions, and neuropeptide Y (NPY), involved in stress responses, was consistently downregulated. Conclusion We identified specific molecular processes in LBD and their interplay with cognitive and motor symptoms, independently of AD pathology. These suggest disruptions in synaptic and cellular regulation. Furthermore, neuropeptides such as NPY may play a neuroprotective role in LBD. These findings contribute to understanding LBD pathophysiology and identifying potential therapeutic targets.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".