With few biomarkers for early identification and limited therapy options for conditions such as Alzheimer's disease (AD) and Parkinson's disease (PD), there is an urgent need for further information about the biology of disease genesis and progression.
Neurodegeneration often progresses silently before diagnosis and is influenced by a variety of systemic variables other than the brain, such as cardiovascular failure, chronic inflammation, oxidative stress, lipid imbalances, synapse loss, endocrine disruption, and so on.
This biological variability has long been a major impediment to creating effective diagnoses and therapies.1,2
To further understand these complex disorders, scalable methods are needed that can profile multiple biological pathways at the same time while maintaining high sensitivity and reproducibility.
These methods are critical for producing early, multifaceted insights and expediting the translation of research into therapeutic benefit.
The following examples demonstrate how Olink's highly scalable Proximity Extension Assay technology aids neurological biomarker research by providing insights into the multifactorial nature of these conditions.
Unraveling complex pathways for early diagnostics and new therapies
Given the accumulating evidence that traditional cardiovascular risk factors increase the likelihood of cognitive impairment and dementia, a new meta-analysis investigated how a diverse set of plasma proteins connected to cardiovascular health are associated with cognitive features.
The findings identified similar connections between cardiovascular disease (CVD) and cognitive reserve or cognitive decline, indicating possible treatment targets to reduce CVD-linked genetic risk.3 Another proteomics investigation on dementia found five important proteins with predictive significance.
Enrichment analysis indicated their participation in immune system pathways, cancer-related processes, and insulin signaling, providing insights into dementia's complex biological foundations and demonstrating proteomics' ability to find novel mechanisms and inform therapeutic strategies.4
In a study on the multifactorial character of early AD, del Campo et al. discovered a group of 12 cerebrospinal fluid proteins capable of detecting disease with high accuracy before amyloid pathology appears.
These proteins were shown to be largely involved in immunological function, as well as processes associated to dopamine biosynthesis, lysosomal activity, and lipid transport, suggesting intriguing new targets for early detection and therapeutic intervention.5
A new large-scale proteomic investigation of Parkinson's disease found that blood-based lipid biomarkers are dysregulated up to 15 years before diagnosis, with consistent decreases and links to prodromal symptoms and brain abnormalities. These findings identify lipid metabolism as a potential early detection target.6
Another investigation of putative Parkinson's disease diagnostic indicators found elevated levels of inflammatory markers, particularly in cognitively impaired patients, indicating a change toward innate immune activation with time.
This shows a relationship between PD progression and chronic neuroinflammation, with a possible breakdown in adaptive immune function contributing to long-term disease severity.7
Chenxu et al. found that several inflammatory proteins may contribute to the advancement of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).
Further investigation revealed that ALS may alter the levels of other immune-related proteins, indicating a potential bidirectional inflammation-disease interaction. These findings highlight ALS's complicated inflammation processes and potential treatment targets.8
Multifaceted insights into response to therapy
A phase II clinical experiment revealed additional insights into the multifactorial etiology of Alzheimer's disease, demonstrating that addressing metabolic imbalances enhanced cognitive performance.
This expands on preclinical research in which mixed metabolic activators (CMA) increased mitochondrial fatty acid oxidation while decreasing oxidative stress, demonstrating their therapeutic potential.9
In a similar PD trial, CMA medication resulted in cognitive gains and positive shifts in metabolic indicators, despite no changes in motor symptoms. Proteomic and metabolomic results showed that CMA improved brain energy metabolism and neuronal function.
Synaptogenesis, inflammation, membrane transport, DNA repair, and protection from oxidative damage and protein aggregation were all impacted. These findings give further evidence that metabolic treatments may boost neural resilience in PD.10
What is next in neurological biomarker research?
Emerging neurodegenerative biomarkers emphasize the importance of looking beyond traditional single-pathway approaches in order to fully understand these complicated disorders.
To capitalize on these findings, sophisticated proteomic techniques will be required, as well as judicious integration with clinical data, imaging, digital health measures, and other omics layers.
References and further reading
- Gutiérrez-Ospina, G., et al. (2022). Editorial: Neurodegenerative Diseases: Looking Beyond the Boundaries of the Brain. Frontiers in Neuroscience, 16. DOI: 10.3389/fnins.2022.929786. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.929786/full.
- Meher Rijwana Afrin., et al. (2025). Advanced Biomarkers: Beyond Amyloid and Tau: Emerging Non-Traditional Biomarkers for Alzheimer’s Diagnosis and Progression. Ageing Research Reviews, pp.102736–102736. DOI: 10.1016/j.arr.2025.102736. https://www.sciencedirect.com/science/article/abs/pii/S1568163725000820.
- Huang, J., et al. (2023). Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study. Frontiers in Genetics, 14. DOI: 10.3389/fgene.2023.1124431. https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1124431/full.
- Gong, J., et al. (2025). Unraveling the role of proteins in dementia: insights from two UK cohorts with causal evidence. Brain Communications. (online) DOI: 10.1093/braincomms/fcaf097. https://academic.oup.com/braincomms/article/7/2/fcaf097/8051152?login=false.
- del Campo, M., et al. (2024). CSF proteins of inflammation, proteolysis and lipid transport define preclinical AD and progression to AD dementia in cognitively unimpaired individuals. Molecular Neurodegeneration, 19(1). DOI: 10.1186/s13024-024-00767-z. https://link.springer.com/article/10.1186/s13024-024-00767-z.
- Gan, Y.-H., et al. (2025). Large-scale proteomic analyses of incident Parkinson’s disease reveal new pathophysiological insights and potential biomarkers. Nature Aging. (online) DOI: 10.1038/s43587-025-00818-0. https://www.nature.com/articles/s43587-025-00818-0.
- Hepp, D.H., et al. (2023). Inflammatory Blood Biomarkers Are Associated with Long-Term Clinical Disease Severity in Parkinson’s Disease. International Journal of Molecular Sciences, (online) 24(19), pp.14915–14915. DOI: 10.3390/ijms241914915. https://www.mdpi.com/1422-0067/24/19/14915.
- Xiao, C., et al. (2024). Two-sample Mendelian randomization analysis of 91 circulating inflammatory protein levels and amyotrophic lateral sclerosis. Frontiers in aging neuroscience, 16. DOI: 10.3389/fnagi.2024.1367106. https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1367106/full.
- Yulug, B., et al. (2023). Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Translational Neurodegeneration, 12(1). DOI: 10.1186/s40035-023-00336-2. https://link.springer.com/article/10.1186/s40035-023-00336-2.
- Yulug, B., et al. (2024). Multi-omics characterization of improved cognitive functions in Parkinson’s disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial. Brain Communications, (online) 7(1). DOI: 10.1093/braincomms/fcae478. https://academic.oup.com/braincomms/article/7/1/fcae478/7943541?login=false.
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