Blood biomarkers for diagnosis and differential diagnosis of Alzheimer's disease in real-world clinical populations: A systematic review.

BackgroundGold standard diagnosis of Alzheimer's disease (AD) relies on invasive, expensive, and non-scalable methods (cerebrospinal fluid lumbar puncture and amyloid-positron emission tomography). Blood biomarkers present a scalable, accessible, and resource-efficient diagnostic alternative.ObjectiveTo investigate the diagnostic and differential diagnostic performance of three clinically relevant plasma biomarkers: phosphorylated tau-217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) for biologically confirmed AD patients in real-world, clinical settings.MethodsA systematic search was conducted across 5 databases for peer-reviewed studies between January 2019-January 2025. A narrative synthesis was conducted for eligible studies.Results13 studies (n = 4686 participants) were included. All studies were cross-sectional, and investigated populations recruited from memory clinics, neurology departments, or clinical cohorts. Diagnostic performance of pTau217 was consistently high (AUC > 0.90 across all comparisons). GFAP showed stronger and more consistent diagnostic performance as compared to NfL, though both demonstrated moderate and variable accuracy (AUCs ranging from <0.75 to >0.90). No studies assessed combinations of all 3 biomarkers. Methodological and assay heterogeneity was common.ConclusionsPlasma pTau217 demonstrated strong diagnostic accuracy and promise for diagnosis of AD. GFAP and NfL displayed inconsistent results, but could provide complementary information, particularly for differential diagnosis. Further standardized studies in underrepresented populations are required to validate and enable blood biomarker implementation in clinical settings.