Blood biomarkers in the early diagnosis of Alzheimer’s disease: an integrative literature review

Abstract

Background: Alzheimer’s disease (AD) is characterized by extracellular amyloid-beta accumulation and intracellular neurofibrillary tangles composed of hyperphosphorylated tau, changes that precede cognitive decline by years. Although diagnostic methods have advanced, gold-standard techniques such as positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis remain limited by cost, invasiveness, and accessibility. In this context, blood-based biomarkers have emerged as a promising alternative, particularly phosphorylated tau (p-tau) isoforms, which closely reflect AD pathophysiology. Evidence indicates these biomarkers not only differentiate AD from other neurodegenerative diseases but also enable detection in preclinical stages. Objective: To analyze evidence on the diagnostic accuracy and clinical applicability of blood biomarkers, emphasizing phosphorylated tau, in early Alzheimer’s disease. Methods: An integrative literature review was conducted using PubMed, SciELO, and Scopus. The descriptors “Alzheimer’s Disease”, “blood biomarkers”, and “phosphorylated tau” were combined using the Boolean operator AND. Observational studies, clinical trials, and systematic reviews published between 2020 and 2025 in English, Portuguese, or Spanish were included. Narrative reviews, case reports, and unrelated studies were excluded. Selection involved title and abstract screening followed by full-text analysis and critical appraisal of the evidence. Results: Thirty-two studies were included, predominantly prospective cohorts and meta-analyses. Plasma p-tau217 consistently demonstrated the highest diagnostic performance, with sensitivity around 88%, specificity 88.7%, and area under the curve (AUC) exceeding 0.90, outperforming other isoforms such as p-tau181. Its accuracy was comparable to established CSF and PET biomarkers (AUC 0.92–0.97), supporting its validity as a surrogate marker of AD pathology. Elevated p-tau217 levels were detected in preclinical stages and increased progressively in amyloid-positive individuals prior to symptom onset. Longitudinal analyses showed associations with neurodegeneration markers, including brain atrophy and cognitive decline, indicating both diagnostic and prognostic value. In contrast, the amyloid-beta 42/40 ratio showed lower performance and greater variability. Combining multiple blood biomarkers improved diagnostic accuracy and may reduce reliance on invasive confirmatory tests. Conclusion: Blood biomarkers, particularly p-tau217, demonstrate high diagnostic accuracy and strong correlation with AD pathology, supporting their role in early diagnosis. Their ability to detect preclinical changes, combined with greater accessibility, highlights their potential for clinical implementation. However, standardization of cut-off values and validation in real-world settings remain essential for routine use.