International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 207 contact with the extracellular environment of brain tissue and is less affected by other factors of the body, the detection of such proteins is considered a reliable basis for early diagnosis (Sur et al., 2025). In recent years, the detection accuracy of cerebrospinal fluid markers has continued to improve. The newly discovered phosphorylated tau types (such as p-tau217 and p-tau205) may have stronger recognition ability and specificity for amyloid protein and tau pathology. However, lumbar puncture is an invasive procedure and has specific requirements for the laboratory environment. These conditions limit the promotion and application of cerebrospinal fluid biomarkers in routine screening (Leuzy et al., 2021). 3.2 Blood biomarkers: research hotspots Blood biomarkers have become a current research hotspot due to their convenient sampling and suitability for large-scale screening. It mainly includes phosphorylated tau (such as p-tau217 and p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), etc. (Leuzy et al., 2021). Plasma p-tau217 and p-tau181 can well distinguish AD from other neurodegenerative diseases and can be used to predict the trend of cognitive decline (Hansson et al., 2023; Chae et al., 2025). NfL reflects the degree of neurodegeneration, while GFAP has a suggesting effect on early amyloid pathology and cognitive decline (Gao et al., 2023; Yang et al., 2023). Analyzing these blood markers together can have a better predictive effect. Its main advantage is that the sampling is simple and no invasive procedures are required. It is very suitable for large-scale screening and long-term disease monitoring (Grande et al., 2025). The current focus of research is to improve the detection steps, with the aim of making its accuracy similar to that of cerebrospinal fluid and imaging methods (Arslan et al., 2024; Sur et al., 2025). 3.3 Emerging biomarkers Some emerging biomarkers, such as exosome micrornas (miRNAs), metabolic markers, as well as digital features like speech analysis and electroencephalogram, have shown potential for early AD identification. Exosomal mirnas in the blood are abnormally expressed in AD patients and can serve as non-invasive and easily accessible markers to help distinguish early AD patients from healthy individuals (Figure 1) (Siedlecki-Wullich et al., 2021; Petracci et al., 2025). Markers based on blood exosomes (including Aβ42, p-tau and various mirnas) can detect pathological changes several years before the onset of clinical symptoms, and their sensitivity is similar to that of cerebrospinal fluid markers (Chen et al., 2022). Metabolic markers, speech patterns, and digital features such as electroencephalograms are also regarded as potential non-invasive screening tools, but their application still needs to be further verified in more people (Klyucherev et al., 2022). These new methods are expected to work better in combination with traditional markers, thereby increasing the technical approaches for the early diagnosis of Alzheimer's disease. 4 Comprehensive Application of Biomarkers for Alzheimer's Disease 4.1 Variability in sensitivity, specificity and accessibility Different biomarkers for Alzheimer's disease (AD) have their own characteristics in terms of sensitivity, specificity and accessibility. For instance, tau protein and beta-amyloid protein markers related to cerebrospinal fluid (CSF) and positron emission tomography (PET) have high diagnostic accuracy. However, due to the invasive nature, high cost and limited popularity of the operation, they are difficult to be promoted in routine clinical practice (Ossenkoppele et al., 2022; Hansson et al., 2023). In contrast, blood biomarkers - such as plasma phosphorylated tau (p-tau), filament light chain (NfL), and glial fibrillary acidic protein (GFAP) - are more accessible and less costly, but their sensitivity and specificity may vary with the disease stage and the type of biomarker used (Figure 2) (Leuzy et al., 2021; Dhauria et al., 2024). Therefore, the selection of which biomarker to choose should be comprehensively considered in combination with the clinical scenario, resource conditions and specific goals (screening, diagnosis or follow-up). 4.2 Combine multiple biomarkers to improve the early detection rate The combined use of multiple biomarkers can effectively improve the accuracy of early Alzheimer's disease (AD)
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