Biofluid-based biomarkers for Alzheimer’s disease: diagnostic and prognostic value across CSF, blood, and saliva in the ATN framework

The escalating global prevalence of Alzheimer’s disease underscores an imperative for the development of accessible, cost-effective, and precise diagnostic strategies. Biofluid biomarkers have consequently become a cornerstone of contemporary dementia research, offering a window into the underlying neuropathology. Although cerebrospinal fluid (CSF) analysis provides the most direct reflection of cerebral pathophysiology and remains the benchmark for biological diagnosis, the pursuit of minimally invasive alternatives has intensified. Remarkable advances in analytical technologies, particularly ultra-sensitive immunoassays and mass spectrometry, have now made it feasible to quantify core AD pathogenic proteins in peripheral blood reliably, and to explore novel biomarkers in even more accessible biofluids such as saliva. This systematic review seeks to synthesize current evidence and evaluate the diagnostic and prognostic utility of biofluid biomarkers in AD. We aim to critically appraise the landscape of established and emerging biomarkers, from well-validated CSF assays to rapidly evolving blood-based biomarkers and pioneering investigations into salivary diagnostics. Our evaluation emphasizes their roles in the differential diagnosis of dementia, the stratification of patients at the prodromal stage, and the longitudinal monitoring of disease progression.