Clinical and laboratory integration in Alzheimer’s disease: From biological biomarkers to diagnostic implementatio

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia world-wide. Traditionally diagnosed based on clinical syndromes, AD is now increasingly defined as a biologically identifiable disease, reflecting advances in fluid and imaging biomarkers. Contemporary diagnostic frameworks emphasize the integration of clinical assessment with biological confirmation and staging, primarily through biomarkers of amyloid-β deposition, tau pathology, and neurodegeneration. This review provides a structured overview of current clinical staging systems and biomarker-based diagnostic approaches in Alzheimer’s disease, with particular emphasis on analytical standardization, interpretive frameworks, and methodological limitations relevant to routine clinical practice. The revised 2024 Alzheimer’s Association criteria are discussed, including the numeric clinical staging model and the AT(N) biomarker classification, which together enable biologically grounded diagnosis independent of symptom severity. Core biomarkers are categorized into Core 1 biomarkers, used for biological confirmation of AD pathology, and Core 2 biomarkers, which characterize disease burden, neurodegeneration, and progression. Cerebrospinal fluid (CSF) biomarkers remain the reference standard for in vivo biological diagnosis, while blood-based biomarkers—enabled by ultrasensitive analytical platforms—have emerged as scalable and minimally invasive tools for screening, risk stratification, and longitudinal monitoring. Multimodal biomarker profiling further supports the identification of mixed or non-Alzheimer comorbid pathologies, which are common in older populations and critically influence clinical interpretation and therapeutic decision-making. Despite their clinical utility, significant challenges remain. Measurement variability related to pre-analytical handling, assay performance, inter-laboratory differences, and lot-to-lot reagent effects continues to limit universal cut-off definition and broad clinical implementation. International standardization initiatives, reference materials, external quality control programs, and automation-ready assays have substantially improved analytical performance, yet pre-analytical variability—particularly for amyloid-β—remains a key unresolved issue. In conclusion, Alzheimer’s disease biomarkers provide a powerful framework for biological diagnosis and staging, but their clinical value increasingly depends on rigorous standardization, harmonization, and context-aware interpretation rather than on the discovery of new markers alone.

Keywords: Alzheimer’s disease, biomarkers, biological diagnosis, diagnostic staging, pre-analytical variability