Advances in ultrasensitive detection technologies for blood-based biomarkers of Alzheimer's disease

Current diagnostic approaches for Alzheimer's disease (AD), including neuroimaging and cerebrospinal fluid (CSF) analysis, are limited by their invasiveness, high cost, and restricted accessibility. In contrast, ultrasensitive blood-based assays overcome these limitations while offering higher patient compliance, making them increasingly attractive. In recent years, substantial progress has been made in identifying blood biomarkers of AD, yet systematic overviews linking these biomarkers to ultrasensitive detection strategies remain limited. To address this gap, this review first discusses the relevance of blood tests to AD pathophysiology and the underlying disease mechanisms, and summarizes blood biomarkers within the established A/T/N framework. We then comprehensively discuss emerging ultrasensitive detection platforms, including single-molecule immunoassay (SiMoA), mass spectrometry, electrochemical biosensors, nucleic acid amplification techniques, surface plasmon resonance (SPR), and optical spectroscopy, focusing on their capabilities to enhance sensitivity and specificity in blood-based AD detection. Notably, we discuss ultrasensitive AD detection strategies from the standpoint of materials engineering and device innovation, revealing how nanomaterials and functional interfaces improve assay performance, thereby addressing a gap not covered by prior clinical or conventional biochemical studies.