Protein Markers of Dementia Risk

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.