Multiplex Approaches for Multifactorial Diseases: A New Era in Neurodegeneration Biomarker Research

With few biomarkers available for early detection, and limited treatment options for conditions like Alzheimer’s disease (AD) and Parkinson’s disease (PD), there is a critical need for deeper insights into the biology of disease onset and progression. 

Neurodegeneration often advances silently before diagnosis and is shaped by a wide array of systemic factors beyond the brain, including cardiovascular dysfunction, chronic inflammation, oxidative stress, lipid imbalances, synaptic loss, endocrine disruption, and more. This biological heterogeneity has long been a key barrier to developing effective diagnostics and therapeutics (1, 2). 

To better understand these complex disorders, we need scalable tools capable of simultaneously profiling multiple biological pathways with high sensitivity and reproducibility. These approaches are essential for generating early, multidimensional insights and accelerating the translation of discovery into clinical impact. The examples outlined below highlight how Olink’s uniquely scalable Proximity Extension Assay technology supports neurological biomarker research by enabling insights into the multifactorial nature of these diseases. 

Unraveling Complex Pathways for Early Diagnostics and New Therapies  

Considering the growing evidence that classical cardiovascular risk factors increase the likelihood of cognitive impairment and dementia, a recent meta-analysis explored how a broad range of plasma proteins linked to cardiovascular health are associated with cognitive traits. The findings revealed shared pathways between cardiovascular disease (CVD) and those for cognitive reserve or affecting cognitive decline, highlighting potential therapeutic targets to mitigate CVD-linked genetic risk (3). 

Another proteomics study in dementia identified five key proteins with predictive value. Enrichment analysis revealed their involvement in immune system pathways, cancer-related processes, and insulin signaling – offering insights into dementia’s complex biological underpinnings and highlighting the potential of proteomics to uncover novel mechanisms and inform therapeutic strategies (4). 

In a study of the multifactorial nature of early AD, del Campo et al. identified a set of 12 cerebrospinal fluid proteins that can detect disease with high accuracy before amyloid pathology becomes apparent. These proteins were linked primarily to immune function, along with pathways related to dopamine biosynthesis, lysosomal activity, and lipid transport—offering promising new targets for early diagnosis and therapeutic intervention (5). 

A recent large-scale proteomic study of Parkinson’s disease revealed that blood-based lipid biomarkers are dysregulated up to 15 years before diagnosis, showing consistent declines and associations with prodromal symptoms and brain changes. These results highlight lipid metabolism as a potential early detection target (6). Another study looking at potential diagnostic markers of PD revealed increased levels of inflammatory markers particularly in cognitively impaired patients, pointing to a shift toward innate immune activation over time. This suggests a link between PD progression and chronic neuroinflammation, with a potential breakdown in adaptive immune function contributing to long-term disease severity (7). 

In another example of inflammation contributing to neurodegenerative disease progression, Chenxu et al. identified several inflammatory proteins as having potential causal links to amyotrophic lateral sclerosis (ALS) disease risk. Further analysis showed that ALS may itself influence levels of other immune-related proteins, revealing a possible bidirectional inflammation–disease interplay. These findings underscore ALS’s complex inflammatory mechanisms and possible therapeutic entry points (8).  

Multifaceted Insights into Response to Therapy 

Further insights into the multifactorial pathology of AD emerged from a phase II clinical trial, showing that correcting metabolic abnormalities improved cognitive function. This builds on preclinical research where combined metabolic activators (CMA) enhanced mitochondrial fatty acid oxidation and reduced oxidative stress, underscoring their therapeutic potential (9). 

In a similar trial for PD, treatment with CMA led to cognitive improvements and favorable shifts in metabolic markers, despite no observed changes in motor symptoms. Proteomic and metabolomic data indicated that CMA positively influenced brain energy metabolism and neuronal function. Affected pathways related to synaptogenesis, inflammation, membrane transport, DNA repair, and protection against oxidative damage and protein aggregation.  These findings provide additional evidence that metabolic interventions may support neurological resilience in PD (10). 

What’s Next in Neurological Biomarker Research? 

Emerging neurodegenerative biomarkers continue to reinforce the need to look beyond traditional single-pathway approaches to fully understand these complex disorders. Harnessing these insights will require robust proteomic tools and thoughtful integration with clinical data, imaging, digital health metrics, and other omics layers. 

There is more to discover on neurological biomarkers. Click here to continue.