Deciphering Alzheimer’s Proteins

A recent study in Cell Genomics has identified seven plasma proteins associated with Alzheimer’s disease (AD), providing new insights into the disease and potential paths for diagnostics. Using a novel method called MR-SPI, researchers combined genetic data and protein structure predictions to uncover biomarkers and explore how genetic mutations alter protein structures.

The study analyzed data from over 54,000 individuals in the UK Biobank and more than 455,000 participants in a genome-wide association study. Seven proteins – TREM2, PILRB, PILRA, EPHA1, CD33, RET, and CD55 – were linked to Alzheimer’s risk. Some, like TREM2, appeared to protect against the disease, while others, like CD33, increased risk. Advanced modeling with AlphaFold3 revealed how mutations in these proteins may disrupt their structure and function. For instance, a mutation in CD33 changes its amino acid composition, potentially affecting how brain immune cells clear amyloid plaques.

MR-SPI, a new statistical approach, allowed the researchers to pinpoint proteins with strong links to Alzheimer’s by selecting reliable genetic markers, even with limited data. This method outperformed existing techniques in accuracy and reliability. These biomarkers could aid in the early detection of Alzheimer’s disease, particularly in individuals with genetic predispositions. Several identified proteins, such as TREM2 and CD33, have known roles in neuroinflammation and amyloid processing, suggesting their utility in developing targeted therapies.

While the study noted some limitations, such as potential biases in pQTL selection and reliance on publicly available GWAS data, it represents a major step forward in understanding the molecular drivers of Alzheimer’s disease. By pinpointing proteins such as TREM2 and CD33 as potential therapeutic targets, this study not only enhances understanding of Alzheimer’s disease pathophysiology, but also opens doors for innovative diagnostic tools, the authors say.