Protein Markers of Dementia Risk

August 02, 2023


Various neurodegenerative disorders and contributing factors play a pivotal role in the pathogenesis of dementia, leading to a gradual and irreversible decline in neuronal integrity and brain function. Early detection of dementia holds significant promise for effective intervention in these severe conditions. Notably, the deposition and aggregation of amyloid-β and tau neurofibrillary tangles within the central nervous system (CNS) have been recognized as crucial hallmarks of Alzheimer's disease (AD). Moreover, emerging evidence indicates that systemic factors and biological processes outside the CNS influence dementia risk. In a recent large-scale study conducted by Walker et al., 2023 and published in Science Translational Medicine, a proteomic signature associated with increased dementia risk has been identified, astonishingly detectable up to two decades before the manifestation of clinical symptoms.

The study included 10,981 participants, of whom 1,874 (17%) developed dementia by the end of the study period. Analysis of 4,877 plasma proteins found 26 proteins significantly associated with 25-year dementia risk. GDF15, a protein that plays a role in metabolic and immunoregulatory functions, exhibited the most significant correlation with the risk of dementia. Follow-up analysis revealed an additional 6 proteins associated near-term (<15 years) and another 6 asscociated with long-term (≥15 years) dementia risk (Table 1). The dementia-associated proteins were found to be predominantly associated with four overlapping biological processes: proteostasis, immunity, synaptic function, and extracellular matrix (ECM) organization.

Fig. IHC of anti-NAG1 antibody (C-terminal specific). Tissue: Human Colon at 20X in colon tissue at pH9. Negative control of human colon tissue pH9 is shown in the background.

Remarkably, several of the leading dementia-associated proteins identified in this study, such as GDF15, were present in low abundance or were undetectable in postmortem brain tissue. Despite their limited presence in the brain, these proteins, along with peripherally secreted proteins and genetic regulators, could still play a crucial role in influencing the expression of genes that show abnormal expression in AD brains. This intriguing discovery highlights the significance of investigating peripheral sources and genetic regulatory mechanisms in understanding the pathogenesis of AD.

The researchers propose that the identified proteins serve as a promising foundation for future investigations, as they hold potential as predictive markers for dementia. Moreover, their findings offer valuable insights into relevant biological pathways, and may aid in the discovery of early-stage markers and underlying molecular factors contributing to the disease.


Dementia-associated Protein Pathway Associated with Dementia Available Antibodies
GDF15 Immune, Metabolism All follow-up times NAG-1 Antibody
NAG-1 Antibody
NAG-1 Antibody
NAG-1 Antibody
NAG-1 Antibody
NAG-1 Monoclonal Antibody
NAG-1 Monoclonal Antibody
NAG-1 Monoclonal Antibody
NAG-1 H Variant Monoclonal Antibody
MMP12 ECM, Immune, Proteostasis 25-year follow-up MMP12 Antibody
EPHA10 Synaptic 25-year follow-up EphA10 Antibody
GLUL Synaptic 25-year follow-up GLUL Antibody
GPLX2 Synaptic 25-year follow-up -
FCRL4 Immune 25-year follow-up FCRL4 Antibody
ABHD14A - 25-year follow-up ABDH14A Antibody
HSPA1B Proteostasis, Immune 25-year follow-up Hsp70 Antibody
HTRA1 Immune, ECM, Metabolism 25-year follow-up HTRA1 Antibody
PSIP1 Immune, Synaptic 25-year follow-up PSIP1 Antibody
GRID2 Synaptic 25-year follow-up GRID2 Antibody
GABARAPL1 Proteostasis 25-year follow-up GABARAPL1 Antibody
SMC3 - 25-year follow-up SMC3 Antibody
MB Vascular 25-year follow-up Mesothelin Antibody
MMP19 ECM, Immune 25-year follow-up MMP19 Antibody
CPLX1 Synaptic 25-year follow-up Complexin 1 Antibody
NDST1 Metabolism 25-year follow-up NDST1 Antibody
DNAJB12 Proteostasis 25-year follow-up DNAJB12 Antibody
CRLF1 Immune 25-year follow-up CRLF1 Antibody
ADAMTSL2 ECM 25-year follow-up ADAMTSL2 Antibody
LEFTY2 Immune 25-year follow-up LEFTY A Antibody
F8 Vascular ≥15 years Factor VIII Antibody
CLSTN3 Synaptic ≥15 years Calsyntenin 3 Antibody
ALB - ≥15 years Human Serum Albumin Antibody
FBLN5 ECM ≥15 years Fibulin 5 Antibody
DNAJB9 Proteostasis ≥15 years DNAJB9 Antibody
CBLN4 Synaptic <15 years CBLN4 Antibody
EGFR Immune, ECM <15 years EGFR Antibody
EGFR Antibody
EGFR phospho Y1197 Antibody
IGFBP2 Metabolism, Immune <15 years IGFBP2 Antibody
GHR Metabolism, Immune <15 years Growth Hormone Receptor Antibody
FAP ECM <15 years Fibroblast Activation Protein Antibody
SERPINA3 Immune, Proteostasis <15 years SERPINA3 Antibody

Table 1: Proteins identified in a proteome-wide association study for 25-year dementia risk.



  1. Walker, K. A., Chen, J., Shi, L., Yang, Y., Fornage, M., Zhou, L., Schlosser, P., Surapaneni, A., Grams, M. E., Duggan, M. R., Peng, Z., Gomez, G. T., Tin, A., Hoogeveen, R. C., Sullivan, K. J., Ganz, P., Lindbohm, J. V., Kivimaki, M., Nevado-Holgado, A. J., Buckley, N., … Coresh, J. (2023). Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Science translational medicine15(705), eadf5681.