Biofluid biomarkers for Alzheimer's disease: past, present, and future

Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease with tremendous social and economic burden. Therefore, early and accurate diagnosis is imperative for effective treatment or prevention of the disease. Cerebrospinal fluid and blood biomarkers emerge as favorable diagnostic tools due to their relative accessibility and potential for widespread clinical use. This review focuses on the AT(N) biomarker system, which includes biomarkers reflecting AD core pathologies, amyloid deposition, and pathological tau, as well as neurodegeneration. Novel biomarkers associated with inflammation/immunity, synaptic dysfunction, vascular pathology, and α-synucleinopathy, which might contribute to either the pathogenesis or the clinical progression of AD, have also been discussed. Other emerging candidates including non-coding RNAs, metabolites, and extracellular vesicle-based markers have also enriched the biofluid biomarker landscape for AD. Moreover, the review discusses the current challenges of biofluid biomarkers in AD diagnosis and offers insights into the prospective future development.