Mendelian Randomization Identifies Plasma Proteins Linked to Neurodegenerative Diseases
Overview
This study used two-sample cis Mendelian randomization and co-localization analyses to identify 50 unique plasma protein–neurodegenerative disease associations, including 23 novel loci. The findings highlight proteins involved in complement, microglia, lysosomes, and blood–brain barrier integrity pathways across Alzheimer’s, Parkinson’s, multiple sclerosis, and amyotrophic lateral sclerosis.
Background
Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and represent a growing global health burden. Proteins play critical roles in biological processes and disease pathogenesis, making them key targets for biomarker discovery and therapeutic intervention. Advances in high-throughput proteomic technologies, including Olink and SomaScan platforms, enable large-scale measurement of plasma protein abundance. Mendelian randomization (MR) using protein quantitative trait loci (pQTLs) allows assessment of potentially causal protein effects on disease risk, overcoming limitations of transcriptome-based approaches.
Data Highlights
Parameter
Value
Number of proteins analyzed
>2700
Protein–disease associations tested
13,377
Significant associations (5% FDR)
169
Protein–disease pairs with co-localization (PP > 0.80)
61
Unique protein–disease associations
50
Novel genetic loci associations
23
Key Findings
Identified 50 unique plasma protein associations with neurodegenerative diseases, with 23 representing novel genetic loci not previously reported by GWAS.
Proteins related to complement system (C1S, C1R), microglia (SIRPA, SIGLEC9, PRSS8), and lysosomes (CLN5) were implicated in Alzheimer’s disease.
Parkinson’s disease associations included proteins in the interleukin-6 pathway (CTF1).
Amyotrophic lateral sclerosis was linked to proteins involved in lysosomes (TPP1), blood–brain barrier integrity (MFAP2), and astrocytes (TNFSF13).
Multiple sclerosis associations involved proteins related to blood–brain barrier integrity (VEGFB), oligodendrocytes (PARP1), nodes of Ranvier and dorsal root ganglion (NCS1, FLRT3, CDH15), and innate immunity (CR1, AHSG, WARS).
APOE plasma abundance was associated with volumes of hippocampus, amygdala, nucleus accumbens, and white matter hyper-intensities; PILRA and PILRB were linked to caudate nucleus volume.
Clinical Implications
These findings provide novel insights into the molecular pathways underlying neurodegenerative diseases and identify new protein targets for biomarker development and therapeutic intervention. The involvement of immune, lysosomal, and blood–brain barrier-related proteins suggests potential avenues for targeted therapies. Integrating proteomic data with genetic analyses enhances understanding of disease mechanisms and may accelerate drug discovery.
Conclusion
Leveraging large-scale genomic and proteomic data through Mendelian randomization reveals novel plasma protein associations with major neurodegenerative diseases, offering valuable targets for future research and clinical translation.
References
Original Study 2024 -- Mendelian Randomization Reveals Protein Associations with Neurodegenerative Disorders
