Highlight
- Blood-based biomarkers (BBMs) are now formally included in diagnostic workflows for Alzheimer’s disease (AD), but should never replace comprehensive clinical evaluation.
- Only BBMs meeting strict sensitivity (≥90%) and specificity (≥75%) criteria are recommended as diagnostic triage tools; higher specificity (≥90%) is required to substitute for CSF or PET confirmation.
- Current guidelines are brand-agnostic, reflecting rapid test evolution and limited head-to-head comparative evidence.
- BBMs promise improved accessibility and prompt diagnosis, but real-world implementation must address pre-analytic, analytic, and interpretive challenges.
Background
Alzheimer’s disease (AD) is the most common cause of dementia globally, affecting over 6 million Americans and exerting profound personal, societal, and economic burdens. Timely and accurate diagnosis remains a core challenge, with traditional methods—clinical assessment, neuropsychological testing, and neuroimaging—often hampered by cost, accessibility, and patient acceptability.
Biomarker-based diagnostics, particularly amyloid and tau PET imaging and cerebrospinal fluid (CSF) analysis, have improved diagnostic accuracy but are limited by invasiveness, cost, and limited availability outside specialized centers. Blood-based biomarkers (BBMs) have emerged as a potentially transformative solution due to their minimal invasiveness, lower cost, and scalability. However, their optimal use, accuracy, and place in clinical algorithms have been unclear.
Study Overview and Methodological Design
In July 2025, the Alzheimer’s Association (AA) released its first clinical practice guideline (CPG) addressing the use of BBMs in the diagnostic workup of AD. This guideline was developed by an expert panel of 11 clinicians from diverse specialties and settings. The panel performed a systematic review of 49 observational studies evaluating 31 distinct BBM tests, focusing on adults with objective cognitive impairment (e.g., mild cognitive impairment [MCI] or dementia) who were candidates for diagnostic evaluation.
Key inclusion criteria for studies were the use of validated BBMs that target plasma phosphorylated tau (p-tau181, p-tau217, p-tau231), amyloid-beta (Aβ42/Aβ40 ratios), and related indices. The primary endpoints were diagnostic test sensitivity, specificity, and clinical utility in identifying underlying AD pathology compared with established CSF or PET standards.
Guideline development followed the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology, ensuring transparent evaluation of evidence quality and recommendation strength. The panel also incorporated feedback from early-stage AD patients, caregivers, and public commentary to ensure patient-centeredness.
Key Findings
The guideline panel reached several evidence-based conclusions:
- BBM tests with sensitivity ≥90% and specificity ≥75% can be used for diagnostic triage in patients with objective cognitive impairment. A negative BBM result can help rule out AD pathology, while a positive result should trigger confirmatory biomarker testing (CSF or amyloid PET).
- BBMs with both sensitivity and specificity ≥90% may serve as alternatives to CSF or PET for diagnostic confirmation, provided rigorous analytic validation in the target population.
- No BBM should be performed prior to comprehensive clinical evaluation by a qualified specialist; results must be interpreted within the entire clinical context.
- The guideline does not endorse any specific BBM assay or platform, citing rapid test evolution and insufficient comparative data.
Statistically, recent meta-analyses suggest that plasma p-tau217, in particular, demonstrates area under the receiver operating characteristic (ROC) curve (AUC) values exceeding 0.90 for distinguishing AD from non-AD pathologies, with some studies reporting sensitivity and specificity both above 90% (Palmqvist S et al., JAMA 2020; Thijssen EH et al., Nat Med 2020). However, performance may vary by clinical setting, assay platform, and population heterogeneity.
Mechanistic Insights and Pathophysiological Context
The core pathophysiology of AD involves accumulation of amyloid-beta plaques and tau neurofibrillary tangles. Traditional CSF and PET biomarkers directly measure these hallmarks. Recent advances enable detection of abnormal phosphorylated tau and amyloid-beta fragments in peripheral blood, reflecting central nervous system (CNS) pathology with high fidelity.
The biological plausibility of BBMs is supported by their correlation with established CSF and PET biomarkers, as well as neuropathological confirmation at autopsy. Plasma p-tau isoforms (notably p-tau217 and p-tau181) are particularly promising, correlating with both amyloid and tau PET status and with rates of cognitive decline.
Clinical Implications
The new guidelines represent a major step toward democratizing AD diagnosis. For clinicians, BBMs can:
- Enable earlier, less invasive triage of patients presenting with cognitive impairment, particularly in primary care or community settings.
- Guide referrals for specialist evaluation or confirmatory testing, improving workflow efficiency and patient experience.
- Potentially expedite access to emerging disease-modifying therapies, which require biomarker-confirmed AD pathology for eligibility.
- Reduce reliance on costly and less accessible neuroimaging or CSF studies, particularly in resource-limited settings.
However, the guidelines emphasize that BBMs should not replace comprehensive clinical assessment and should only be ordered by or in consultation with AD specialists. Test results must be integrated with cognitive, functional, and imaging data to ensure accurate diagnosis and avoid misclassification.
Limitations and Controversies
Despite their promise, BBMs face notable challenges:
- Analytic variability: Commercial BBM assays differ in targets, platforms, and cutoff thresholds, complicating standardization and cross-platform comparisons.
- Pre-analytical factors: Specimen handling, comorbidities (e.g., chronic kidney disease), and demographic factors (e.g., race/ethnicity) may influence biomarker levels.
- Lack of head-to-head validation: Few studies directly compare leading BBM assays in diverse, real-world populations.
- Interpretive complexity: Test performance may decline outside specialized centers, and the positive predictive value of BBMs is lower in populations with low AD prevalence.
Additionally, ethical and psychosocial considerations—such as patient anxiety, stigma, and implications for insurability—must be addressed as BBMs enter wider clinical use.
Expert Commentary or Guideline Positioning
Dr. Sheena Aurora, Vice President of Medical Affairs at the Alzheimer’s Association, notes: “The broad adoption of the Alzheimer’s Association’s CPG on blood biomarkers by specialists could lead to quicker and more accurate diagnoses, as well as better outcomes for individuals and families affected by Alzheimer’s.”
Dr. Maria C. Carrillo, Chief Science Officer at the AA, adds, “Adoption of these recommendations will lead to quicker, more accessible, more accurate diagnoses and better outcomes for individuals and families.”
The guidelines are available via the Alzheimer’s Association’s ALZPro platform. Forthcoming updates will address cognitive assessment tools, clinical staging and treatment, and prevention strategies, reflecting the rapidly evolving nature of the field.
Conclusion
The Alzheimer’s Association’s inaugural CPG for blood-based biomarkers marks a transformative advance in the diagnostic approach to AD. While BBMs offer remarkable potential to improve diagnostic equity and efficiency, their use must be guided by robust accuracy standards, comprehensive clinical evaluation, and ongoing evidence generation. Future research should focus on assay harmonization, validation in real-world and diverse populations, and integration with digital and imaging biomarkers. As the field evolves, clinicians should remain vigilant, ensuring patient-centered, evidence-based care.
References
- Alzheimer’s Association. Clinical Practice Guideline for Blood-Based Biomarker Tests. https://aaic.alz.org/releases-2025/clinical-practice-guideline-blood-based-biomarkers.asp. Accessed July 29, 2025.
- Palmqvist S, Janelidze S, Stomrud E, et al. Performance of fully automated plasma assays as screening tests for Alzheimer disease–related β-amyloid status. JAMA. 2020;324(7):1-11. doi:10.1001/jama.2020.12134
- Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med. 2020;26(3):387-397. doi:10.1038/s41591-020-0762-2
- Hansson O. Biomarkers for neurodegenerative diseases. Nat Med. 2021;27(6):954-963. doi:10.1038/s41591-021-01382-x
