Global Neurodegeneration Proteomics Atlas Reveals Key Disease Signatures

From loss of their memory to their muscle control, more than 57 million people worldwide face devastating consequences from neurodegeneration. However, treatment options remain limited. 

To address this critical global need for early diagnosis and treatment, a groundbreaking public–private partnership was formed in 2023, called the Global Neurodegeneration Proteomics Consortium (GNPC). 

Just two years later, the GNPC has publicly released one of the world's largest harmonized proteomics datasets for neurodegenerative diseases. It includes data from more than 35,000 biofluid samples, leading to approximately 250 million unique protein measurements. 

The neurodegenerative diseases in this dataset represent some of the most challenging medical conditions due to their complex, overlapping yet distinct pathological mechanisms. 

Through comprehensive proteomic analysis, the GNPC aims to discover both disease-specific and shared biomarkers that can advance early diagnosis and understanding of disease mechanisms. 

A consortium of 23 global research institutes

The GNPC is a consortium of 23 global research institutions, including academic, government, and industry partners. It collects proteomic data from multiple cohorts of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and healthy aging populations, and harmonizes it into a single dataset. 

The data is measured from plasma, cerebrospinal fluid, and serum biospecimens using advanced proteomic platforms such as SomaScan, Olink Explore HT, Alamar Biosciences’ NULISA, and mass spectrometry. This integration allows for broad, multi-disease comparisons as well as disease-specific biomarker discovery.

“It is very exciting to be part of the consortium as it brings together dozens and dozens of brilliant scientists working together and bringing their unique expertise to better understand the main neurodegenerative diseases,” said Alexa Pichet Binette, PhD, assistant professor at the University of Montreal in Canada. 

Binette has been working with the consortium for the last couple of years to understand proteomic differences between neurodegenerative diseases.

Cross-disease and shared signatures

Neurodegenerative diseases exhibit distinct yet overlapping pathological mechanisms. 

Leveraging large-scale plasma proteomics data from the GNPC, shared and disease-specific proteins were identified that could promote discovery of future diagnostic biomarkers and drug targets. 

This work validated many known disease-associated proteins and biomarkers, as well as allowed for the discovery of novel, not previously implicated proteins in neurodegeneration. 

Furthermore, the consortium identified a subset of proteins elevated across Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia, revealing immune system activation, disrupted energy metabolism (notably glycolysis), and extracellular matrix (matrisome) as shared disease signatures, portraying neurodegeneration as a network disorder rather than isolated events.

Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive brain disorder that slowly affects memory and cognitive skills, eventually impairing the ability to carry out everyday tasks. 

From almost 2,000 cases in the GNPC dataset, 5,187 proteins were significantly associated with AD. Apoptotic processes were uniquely enriched in AD, highlighting the disease’s distinct molecular pathology. 

There was also a pronounced downregulation of synaptic and vesicle trafficking proteins, suggesting a fundamental disruption of neuronal communication and synaptic function. This downregulation involves proteins critical to synaptic vesicle cycling, neurotransmission, and endocytic trafficking pathways, reflecting the synaptic loss central to AD pathology. 

Dysregulation of these presynaptic and postsynaptic proteins aligns with altered intracellular trafficking and contributes to cognitive deficits. Altogether, AD pathology involves apoptosis, and disruption in protein transport and synaptic signaling.

Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurological disorder characterized by tremors, muscle stiffness, slowness of movement, and impaired balance due to loss of dopamine-producing brain cells. 

A quantitative analysis of around 600 PD samples found 3,748 proteins associated significantly with PD. PD exhibits impairment in endoplasmic reticulum–phagosome pathways, distinctive to its molecular pathology. 

As expected based on the known literature, there was dysregulation of the ubiquitin–proteasome system and improper protein phosphorylation. Distinct elevations in inflammatory proteins and members of the Ras-family proteins involved in cellular signaling aligned with chronic neuroinflammation and disrupted intracellular communication mechanisms that are characteristic of PD. 

These proteomic signatures differentiate PD from AD and FTD, highlighting its unique inflammatory and immune profile. 

Frontotemporal dementia

Frontotemporal dementia (FTD) is a group of disorders caused by progressive nerve cell loss in the brain’s frontal and temporal lobes, leading to changes in personality, behavior, and language. 

Across less than 200 samples, FTD exhibits unique proteomic deficits that are largely non-overlapping with those observed in AD or PD, indicating distinct molecular underpinnings. These include specific alterations in proteins involved in cellular homeostasis, RNA processing, and cytoskeletal dynamics. 

The proteome signature of FTD suggests pathways such as RNA splicing and lysosomal function are particularly disrupted, highlighting its unique pathological trajectory compared to AD and PD.

The APOE4 signature

Other than being recognized as the strongest genetic risk factor for late-onset AD, APOE ε4 has also been implicated in related neurodegenerative diseases. 

APOE ε4 is a variant of the apolipoprotein E gene that is essential for lipid and cholesterol transport as well as metabolism. APOE proteins are involved broadly in redistributing lipids to neurons and glial cells, facilitating synapse formation, neurite growth, and synaptic plasticity important for healthy brain function. Though APOE ε4 is linked to increased risk of neurodegeneration, its normal functions in lipid homeostasis and neuronal signaling necessary for brain and systemic health. 

Researchers at the GNPC analyzed 1,346 cerebrospinal fluid and 9,924 plasma samples to reveal an APOE ε4 proteomic signature shared between AD, FTD, PD, PD dementia (PDD), amyotrophic lateral sclerosis, and nonimpaired controls. The signature is associated with increased activity in immune and inflammatory pathways, including cell types such as monocytes, T cells, and natural killer cells.

A consistent APOE ε4 phenotype of aggregation of certain proteins and gliosis was observed across sample types and neurodegenerative disease, highlighting a biological vulnerability to neurodegeneration. 

Overall, these findings reposition APOE ε4 away from being only an AD risk factor toward it being a broad immune modulator that interacts with environment and lifestyle factors to modulate biological vulnerability to neurodegeneration. Thus, APOE ε4 is necessary but not sufficient for neurodegeneration.

Aging and proteomic clocks

Other than identifying risk factors, by comparing predicted organ age to chronological age, the GNPC dataset can reveal patterns of accelerated biological aging. 

Proteomic profiling revealed age-related increases in permeability-associated proteins, such as complement components and vascular factors, that may preserve cognitive function but reflect disruption of the blood-brain barrier. 

Genome-wide studies link specific genetic loci to variations in protein blood-brain transport, suggesting new biological targets for brain-permeable therapeutics. Overall, such proteomic aging clocks provide minimally invasive biomarkers that could monitor organ health, track disease progression, and guide interventions before clinical symptoms arise.

Future biomarkers for neurodegenerative disease

Taken together, the GNPC is pioneering early detection tools and comprehensive biomarker panels across multiple neurodegenerative diseases through its harmonized, large-scale dataset. 

Continued validation and mechanistic studies will be needed to translate these findings into clinical practice. The consortium plans ongoing data releases and expansion, publicly sharing data to accelerate research and therapeutic development for millions affected worldwide.

Binette commented, “Given the heterogeneity and complexity of neurodegenerative diseases, it's a great advantage to have a such a large and diverse dataset like GNPC’s¾both in terms of the number of sites involved as well as the large-scale proteomics data. It can really help to capture shared and unique signatures across diseases, potentially discover novel biomarkers or identify altered biological pathways to target in future therapeutics development. It's amazing to have this dataset available publicly at no costs to accelerate discoveries.”

Indeed, the GNPC’s harmonized proteomics dataset is an unparalleled resource enables an unprecedented discovery of protein biomarkers and mechanistic pathways, with the potential to revolutionize diagnosis and therapeutic development.