Transdiagnostic proteomics examines shared protein alterations across multiple neurodegenerative diseases, revealing common molecular pathways that transcend traditional diagnostic boundaries. Large-scale proteomic studies have identified conserved signatures in Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD), suggesting common underlying mechanisms of neuronal vulnerability and glial dysfunction[1].
Multiple studies have identified a core set of proteins consistently altered across neurodegenerative conditions:
While some protein changes are disease-specific, others represent a common "neurodegenerative proteomic signature"[2]:
| Category | Shared Changes | Disease-Specific |
|---|---|---|
| Immune | C3, C4, TREM2, complement factors | Disease-specific cytokine patterns |
| Synaptic | SNAP25, synaptophysin reduction | PSD95 alterations in AD |
| Lysosomal | LAMP1/2, cathepsins | GBA variants in PD |
| Metabolic | Glycolysis enzymes | Complex I in PD |
The APOE ε4 allele represents the strongest genetic risk factor for AD and influences neurodegeneration across diagnostic categories. Proteomic studies have identified distinct signatures in ε4 carriers[3]:
Key findings in APOE ε4 carriers:
CSF studies in APOE ε4 carriers reveal[5]:
APOE ε4 effects extend beyond AD to[6]:
The complement system represents a central hub of transdiagnostic proteomic changes[7]:
Upregulated in multiple diseases:
Implications:
Proteomic studies consistently identify microglial alterations[8]:
| Protein | AD | PD | FTD | Function |
|---|---|---|---|---|
| TREM2 | ↑ | ↑ | ↑ | Phagocytic receptor |
| CD33 | ↑ | Variable | ↑ | Siglec receptor |
| CX3CR1 | ↓ | ↓ | ↓ | Fractalkine receptor |
| IBA1/AIF1 | ↑ | ↑ | ↑ | Microglial marker |
Transdiagnostic cytokine signatures include[9]:
Network analysis reveals conserved molecular modules across neurodegenerative conditions[10]:
Common to AD, PD, FTD, and ALS:
Shared autophagy/lysosome changes:
Energy metabolism commonalities:
Transdiagnostic proteomic signatures have diagnostic and prognostic utility[11]:
| Biomarker | Cross-Disease Relevance |
|---|---|
| Neurofilament light chain (NfL) | AD, PD, FTD, ALS |
| YKL-40 | AD, PD, FTD |
| TREM2 | AD, FTD |
| GFAP | AD, PD |
Understanding transdiagnostic proteomic changes identifies shared therapeutic targets[12]:
While shared mechanisms exist, disease-specific approaches remain important:
Bai B, et al. Deep multiverse proteomics reveals transdiagnostic molecular signatures across neurodegenerative diseases. Nature Neuroscience. 2023. ↩︎
Zhou Y, et al. Human brain proteomics reveals shared and distinct patterns across neurodegenerative diseases. bioRxiv. 2023. ↩︎
Zhou M, et al. APOE4 affects brain proteome in cognitively normal adults independent of amyloid. Neurology. 2023. ↩︎
Shi Y, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017. ↩︎
Cruchaga C, et al. Cerebrospinal fluid proteomics in APOE4 carriers and non-carriers. JAMA Neurology. 2013. ↩︎
Tsuang D, et al. APOE affects neurodegeneration in Parkinson's disease. Neurology. 2013. ↩︎
Morgan BP. Complement in the pathogenesis of Alzheimer's disease. Nature Reviews Neurology. 2021. ↩︎
Yeh FL, et al. TREM2 functions as a receptor for amyloid-beta. Neuron. 2022. ↩︎
Chen X, et al. 'Cytokine profiles in neurodegenerative diseases: A transdiagnostic meta-analysis'. Brain. 2021. ↩︎
Seyfried NT, et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer's disease. Cell Systems. 2017. ↩︎
Blennow K, et al. Neurofilament light as a biomarker in neurodegenerative disorders. Nature Reviews Neurology. 2020. ↩︎
Zhang Y, et al. Therapeutic targeting of transdiagnostic mechanisms in neurodegenerative disease. Trends in Neurosciences. 2024. ↩︎