Alzheimer's disease (AD) is the most common form of dementia and a leading cause of death among the elderly. Limited understanding of its complex pathologies has hindered the development of effective diagnostics and treatments. Recently approved anti-amyloid drugs have brought new hope for AD treatment, particularly in individuals with early-stage disease and amyloid pathology. Recognizing the immense promise of blood biomarkers for early diagnosis, we conducted large-scale blood proteomics studies of AD and mild cognitive impairment (MCI) in collaboration with local clinicians. We identified hundreds of blood protein biomarkers associated with AD/MCI, which are involved in various biological pathways. From these, we selected representative proteins to generate a "blood protein signature of AD." This work led to the development of a novel blood-based multiple protein biomarker test for early detection and monitoring of AD. This innovative blood test accurately indicates the presence of brain amyloid pathology, even at its early stages. When used alongside artificial intelligence machine learning and the UK Biobank database, the test is able to predict the risk of AD 15 years before clinical diagnosis. Additionally, we identified several blood protein biomarkers as therapeutic targets for drug development, including soluble ST2 (sST2), a decoy receptor for the cytokine interleukin 33. Blood levels of sST2 are elevated in AD patients. In an AD transgenic mouse model, increased sST2 levels worsen AD pathology by impairing the microglia-mediated clearance of toxic amyloid-beta, a key pathological process in AD. We have developed novel sST2 modulators, including small molecules and RNA-based therapeutics, as potential treatments. Our research on blood protein biomarkers underscores the importance of human studies in discovering new diagnostics and therapeutic strategies.
