Abstract

Background
Alzheimer disease (AD) is the most common cause of dementia in the world and its prevalence is increasing and it has important public health consequences. Early diagnosis remains challenging due to reliance on costly and invasive methods such as positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis. Blood-based biomarkers have emerged as a promising, less invasive alternatives to identify AD pathology, especially in the early and preclinical stages. This systematic review aim to evaluate the diagnostic accuracy of blood-based biomarkers for the early detection of Alzheimer’s disease.

Methods
An extensive literature search was performed in PubMed/MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library on studies published since 2010 up to March 2026. The search strategies involved the use of Medical Subject Headings (MeSH), and free-text words associated with Alzheimer disease, blood-based biomarkers, and diagnostic accuracy. Peer-reviewed diagnostic accuracy studies focused on adult populations were included in line with PICO framework. The selection of studies was based on PRISMA guidelines and were critically appraised using QUADAS-2. Because of heterogeneity across the included studies, synthesis of findings was carried out using a narrative approach.

Results
Six studies were included in this review. Diagnostic performance of phosphorylated tau biomarkers (p-tau181 and p-tau217) was consistently high (AUC up to 0.93), and glial fibrillary acidic protein (GFAP) also showed strong performance (AUC up to 0.87). Amyloid-β ratios (Aβ42/Aβ40) showed moderate to high accuracy, especially in preclinical detection, but had varying performance across assays (AUC 0.69–0.94). Neurofilament light chain (NfL) demonstrated moderate diagnostic value (AUC of up to 0.79) and was more predictive of progression than an early diagnosis. Combinations of biomarkers, especially those that included genetic variables like APOE genotype, were consistently more effective than individual biomarkers (AUC up to 0.92).

Conclusion
Biomarkers in blood, especially p-tau and GFAP, have a strong potential for early detection of Alzheimer disease, with their combination yielding better results. Although promising, assay variation and lack of standardisation hinder clinical translation. To facilitate their integration into standard diagnostic practice further large-scale validation and harmonisation effort is required.