Wang_2025_Biosens.Bioelectron_287_117722

Alzheimer's disease (AD) is the prevalent neurodegenerative disorder characterized by the accumulation of aberrant proteins that obstruct brain cells and neurons. Early detection of Alzheimer's disease-related biomarkers is very critical for effective treatment of AD. However, the current probes for early clinical diagnosis of AD are invasive and costly, susceptible to interference by biological background fluorescence, and lack sufficient penetration capabilities and challenges associated with imaging in vivo. Therefore, it is very important to develop small-molecular fluorescent probes with biocompatibility, strong penetration ability of the blood-brain barrier (BBB), customizable physical and chemical properties, and real-time non-destructive in situ monitoring. This review provides a comprehensive overview of protein aggregates, reactive oxygen species, metal ions, gas markers, cholinesterase, cysteine, and other recently discovered biomarkers, concentrating on the mechanism of targeted diagnosis and the relationship between probe structure and characteristics. In addition, the review also summaries recent advances in machine learning and artificial intelligence for AD field. Furthermore, the challenges and prospects of small-molecule fluorescent probes for AD diagnosis and clinical application are also summarized. This review aims to provide a foundation for researchers in this field, stimulate innovative molecular design strategies, expedite the clinical evaluation of AD probes, and ultimately achieving accurate early detection of AD.