International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 209 applications, multimodal approaches have been widely recognized as key methods for improving clinical trial design, screening subjects, and evaluating intervention effects (Ossenkoppele et al., 2022; Jiao et al., 2024). Figure 2 Most promising plasma-based biomarkers across the clinical continuum of AD (Adopted from Leuzy et al., 2021) 5 Challenges in Alzheimer's Disease Research 5.1 The detection methods did not uniformly limit the reproducibility of the study At present, a consistent operating procedure has not been established, resulting in significant differences in biomarker measurements among different laboratories and institutions. Variables such as sample processing methods, reagent sources and detection platforms may introduce errors, affect the credibility of the results, make the data difficult to compare directly, and also hinder the establishment of a unified clinical judgment standard. Even minor deviations during the detection process can significantly weaken the clinical judgment value of biomarkers, especially when the variation range is small, such as the plasma Aβ42/40 ratio (Altomare et al., 2023). Because there is no cross-center validation and standardized operating procedures-which are necessary for applying research results to clinical practice-it is more difficult to repeat the research. The test results vary at different times or in different laboratories, and it is necessary to establish reference ranges suitable for different populations. All these indicate the need for unified norms to ensure consistent and accurate interpretation of biomarkers. 5.2 Cost, equipment and ethical factors limit clinical translation Advanced diagnostic methods such as PET imaging and cerebrospinal fluid testing are costly and have limited popularity, which restricts their wide application in primary care and resource-poor areas (Ossenkoppele et al., 2022). Although blood biomarkers offer better cost-effectiveness and are easier to promote, to achieve accurate detection and result interpretation, corresponding resources still need to be invested in equipment configuration, personnel training and infrastructure. When informing biomarker results, especially among people with normal cognition, there are ethical issues, such as the uncertainty of whether the disease will progress, which may cause psychological stress. In addition, there are still disputes over how to correctly use biomarker data to assist clinical judgment, inform and consent to patients, and handle cases of unexpected detections. All these issues require clear guiding rules and a patient-centered communication approach (Arslan et al., 2024). 5.3 Population heterogeneity affects the universality and accuracy of biomarker results The expression and interpretation of biomarkers for Alzheimer's disease are susceptible to population differences, including race, age, comorbidiasis and socioeconomic status, etc. Most existing biomarker studies are based on strictly screened subject populations, which may not fully reflect the diversity of the real clinical population, leading to a decline in the effectiveness of the conclusions when widely applied, and even misjudgment (Ossenkoppele et al., 2022).
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