Emerging blood biomarkers in Alzheimer's disease: a proteomic perspective

Early detection of Alzheimer's disease (AD) remains a formidable clinical challenge, but emerging blood-based assays show promise for identifying at-risk individuals long before cognitive symptoms arise. This is the first comprehensive synthesis comparing mass-spectrometry and immunoassay platforms across multiple blood-based AD biomarkers and the first to integrate these findings into a unified roadmap for clinical implementation. In this review, we compare high-throughput mass spectrometry and ultrasensitive immunoassays for quantifying circulating amyloid-β isoforms, phosphorylated tau species (p-tau181, p-tau217), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), YKL-40 and selected inflammatory markers. Individual biomarkers demonstrate diagnostic accuracies (AUC) up to 0.90, and integrating these protein signatures with APOE ε4 genotype, brief cognitive assessments and neuroimaging via machine-learning models boosts discrimination of preclinical AD from normal aging to over 80% accuracy. We trace the path from initial discovery through analytical validation to clinical implementation, emphasizing critical hurdles such as variability in sample collection, limited cohort diversity and regulatory requirements. Future work must standardize preanalytical protocols, extend validation across populations, refine ultrasensitive detection techniques, and combine proteomic data with genomics and other "omics" layers to move toward routine blood-based screening. These coordinated efforts provide a clear roadmap for transforming early AD diagnosis and enabling timely, personalized interventions.