The evolving landscape of Alzheimer’s disease testing: A clinical laboratory perspective on emerging diagnostics

Alzheimer’s disease (AD) remains one of the most pressing public health challenges, with millions affected worldwide and numbers expected to rise. Early and accurate diagnosis of AD is critical for enabling access to emerging treatments, care planning, and supporting symptom management. Identifying the disease in its preclinical or early symptomatic stages allows clinicians to initiate interventions that may slow progression, manage symptoms more effectively, and improve quality of life. It also enables patients and families to make informed decisions about future care, legal and financial planning, and participation in clinical trials.

From a therapeutic standpoint, early diagnosis is increasingly important as disease-modifying treatments become available, many of which are most effective when administered before significant neurodegeneration has occurred. For clinical laboratories, this underscores the value of reliable, accessible testing methods that can support timely and precise diagnostic workflows.

As the demand for early and accurate diagnosis grows, clinical laboratories are increasingly positioned at the forefront of innovation—transitioning from peripheral roles to central players in neurodegenerative disease diagnostics.

From imaging to biomarkers: A shifting diagnostic landscape

Historically, AD diagnosis has relied on clinical assessments, neuropsychological testing, and advanced imaging techniques. Amyloid and tau PET scans provide direct measures of amyloid and tau pathology, while MRI is primarily used to assess structural and functional brain changes associated with neurodegeneration. Although informative, these methods are costly, invasive, and often inaccessible to many patients. Cerebrospinal fluid (CSF) analysis, another cornerstone of AD diagnostics, offers high diagnostic accuracy but requires lumbar puncture and specialized handling—limiting its scalability and routine use.

Because of these methodological constraints, clinical laboratories have traditionally played a limited role in these diagnostic workflows. However, the emergence of blood-based biomarkers is reshaping this landscape, promising scalable and minimally invasive tools that can complement, and in some contexts reduce reliance on, imaging and CSF testing.

Blood-based biomarkers: A new frontier for labs

For many years, scientists, clinicians, and diagnostic companies have been searching for an easier way to identify AD. Recent advances have identified key plasma biomarkers that reflect AD pathology with high accuracy. For example, plasma tau phosphorylated at amino acid 217 (p-Tau217) has shown similar sensitivity and specificity to CSF for identifying tau and amyloid pathologies,¹ which mirrors study findings (although accuracy may vary across settings). p-Tau217 has been observed to rise decades before cognitive symptoms and may precede detectable tau accumulation on PET.²

When used in combination, biomarkers have the potential to offer diagnostic accuracy comparable to amyloid PET imaging, which can be especially beneficial for cognitively unimpaired individuals. A ratio of p-Tau217, a marker of tau pathology, and amyloid beta 1-42 (Aβ1-42), a marker of amyloid accumulation, in the brain, has shown high accuracy (with positive and negative predictive values (PPV and NPV) ≥90%) for detecting amyloid pathology.³

In May 2025, the U.S. Food and Drug Administration granted clearance for the first blood test designed to aid in the detection of amyloid plaques—a hallmark of AD—in adults 55 and older who exhibit symptoms of cognitive decline. In clinical studies, this assay, the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test, demonstrated a positive predictive value of ~92% and a negative predictive value of ~97%, showing strong concordance with PET and CSF results and marking a major milestone in AD diagnostics.⁴

In July 2025, the Alzheimer’s Association issued the first evidence-based clinical practice guidelines focused on the use of blood-based biomarker tests to “assess levels of Alzheimer’s disease pathology in people with cognitive impairment.”⁵

The new guidelines currently only apply to patients with mild cognitive impairment who are being seen for memory disorders, and the test must meet certain criteria to apply:

• “BBM tests with ≥90% sensitivity and ≥75% specificity can be used as a triaging test, in which a negative result rules out Alzheimer’s pathology with high probability. A positive result should also be confirmed with another method, such as a cerebral spinal fluid (CSF) or amyloid positron emission tomography (PET) test.
• “BBM tests with ≥90% for both sensitivity and specificity can serve as a substitute for PET amyloid imaging or CSF Alzheimer’s biomarker testing.”⁵

Note that these recommendations apply exclusively to patients with objective cognitive impairment presenting to specialized memory care settings and should always be interpreted within the broader clinical context, with attention to test performance variability.

Challenges and considerations for laboratory implementation

Despite their promise, blood-based biomarkers are not without challenges. Standardization of pre-analytical methods and guidelines for assessing these biomarkers will be required for consistent and reliable integration into clinical practice.^6,7 Labs integrating AD biomarker must consider factors such as pre-analytical differences; biological variability, including age, sex, APOE ε4 carrier status; and interpret results in light of comorbidities such as kidney disease.⁸

Pre-analytical variables

Before the sample ever reaches the machine, variables such as the sample type (plasma vs. serum), collection tube type (e.g., K₂EDTA versus K₃EDTA versus lithium heparin versus sodium citrate), mixing ratios, and processing time can significantly impact results.⁹

For example, amyloid beta (Aß) is a relatively sticky protein. Tubes that minimize proteolytic degradation and reduce protein binding to the surface of the tube (which can lead to artificially low levels of Aß) can decrease peptide degradation, improving accuracy.^9,10 Similarly, the stability of certain biomarkers is highly dependent on proper pre-analytical handling and storage temperature of blood samples.^11,12

Regulatory compliance

Other than the aforementioned Lumipulse assay, plasma-based assays remain research use only (RUO) or are laboratory-developed tests (LDT). Tests must meet CLIA standards and, where applicable, FDA clearance or LDT validation under CLIA. Understanding the sensitivity and specificity of available assays—be they RUO assays or already approved—can aid in the understanding of test reliability. This is essential for evaluating diagnostic utility, minimizing false positives or negatives, and guiding clinical decision-making and research applications.⁷

Assay validation

Test sensitivity, specificity, and reproducibility must be evaluated and verified. Similarly, calibration, reference ranges, and inter- and intra-lab harmonization are essential for clinical reliability.

Misdiagnosis can lead to ineffective or potentially harmful treatments, unnecessary emotional distress, and exclusion from clinical trials that could offer therapeutic benefits.¹³ Labs and clinicians must be aware of the psychological impact of early diagnosis and ensure results are communicated accurately and responsibly.^14,15

Workflow integration and clinical impact

With complex texting and increasing demand, laboratories must consider how blood-based biomarker tests fit into their broader clinical workflows:

• Analyzers and automation: Advantaged workflows, driven by advanced technologies, automation, and high-sensitivity analyzers, can streamline operations, reducing errors, manual touchpoints, and repetitive steps
• Ordering and reporting: Clear guidelines for patient preparation (e.g., fasting status, time of day¹⁶), test use (e.g., cognitive screening, differential diagnosis, eligibility for disease modifying therapies), and result interpretation (relative to things like disease stage and comorbidities) are needed to support clinicians
• Data integration: Results should be compatible with laboratory information systems (LIS) and electronic health records (EHR) systems to enable longitudinal tracking (needed for monitoring disease progression) and decision support (needed for evidence-based recommendations)
• Clinical utility: Biomarker testing can help identify patients eligible for disease-modifying therapies and help reduce reliance on more invasive and costly procedures such as imaging and CSF testing

Looking ahead: The future of AD testing in labs

As our understanding of AD and other dementias grows and more biomarkers become available, we will be better equipped to identify individuals at risk and monitor disease progression. Simultaneously, our reliance on the expertise of the clinical laboratory staff for translating results into actionable diagnostic data will grow. Collaborative models involving partnerships between clinical labs, neurology clinics, biomarker manufacturers, research institutions, and pharmaceutical companies will be essential for refining testing protocols, validating new assays, and ultimately improving patient outcomes through more integrated and personalized diagnostic strategies.

Conclusion

Blood-based biomarkers represent a turning point in Alzheimer’s disease diagnostics, and clinical laboratories are poised to play a transformative role, fundamentally reshaping the future of dementia care. Continued research, education, innovation, and ethical deployment are essential to maximizing the impact of these biomarkers. Working with the assay developer to establish comprehensive training for personnel regarding the challenges of implementing AD blood-based biomarkers will position clinical laboratories for success in the ever-evolving landscape of AD diagnostics.

References

1.   Khalafi M, Dartora WJ, McIntire LBJ, et al. Diagnostic accuracy of phosphorylated tau217 in detecting Alzheimer's disease pathology among cognitively impaired and unimpaired: A systematic review and meta-analysis. Alzheimers Dement. 2025;21(2):e14458. doi:10.1002/alz.14458. 

2.   Jonaitis EM, Janelidze S, Cody KA, et al. Plasma phosphorylated tau 217 in preclinical Alzheimer's disease. Brain Commun. 2023;5(2):fcad057. doi:10.1093/braincomms/fcad057.

3.   Wynveen P, Lengfeld J, Lim HK, et al. Performance of the Beckman Coulter prototype plasma p-Tau217 and p-Tau217/Aβ42 ratio assays in a cohort of individuals with cognitive impairment. Poster presented at the: AAIC 2025; July 28, 2025; Toronto, CA.

4.   FDA clears first blood test used in diagnosing Alzheimer’s disease. FDA. May 16, 2025. Accessed September 23, 2025. https://www.fda.gov/news-events/press-announcements/fda-clears-first-blood-test-used-diagnosing-alzheimers-disease.

5.   Alzheimer’s Association releases its first clinical practice guideline for blood-based biomarker tests. Alzheimer’s Association. July 29, 2025. Accessed September 23, 2025. https://aaic.alz.org/releases-2025/clinical-practice-guideline-blood-based-biomarkers.asp.

6.   O'Bryant SE, Gupta V, Henriksen K, et al. Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research. Alzheimers Dement. 2015;11(5):549-60. doi:10.1016/j.jalz.2014.08.099. 

7.   Mielke MM, Anderson M, Ashford JW, et al. Considerations for widespread implementation of blood-based biomarkers of Alzheimer's disease. Alzheimers Dement. 2024;20(11):8209-8215. doi:10.1002/alz.14150. 

8.   Torres-Torronteras J, Gouda M, Teunissen CE, Verberk IMW, del Campo M. Impact of pre-analytical factors on fluid biomarker measurements in Alzheimer disease. In: Biomarkers of Neurodegenerative Disorders. Springer Nature Switzerland; 2025:475-496.

9.   Alcolea D, Beeri MS, Rojas JC, Gardner RC, Lleó A. Blood biomarkers in neurodegenerative diseases: Implications for the clinical neurologist. Neurology. 2023;101(4):172-180. doi:10.1212/WNL.0000000000207193. 

10.  Chen Y, Zeng X, Lee J. Improving the preanalytical stability of Alzheimer’s disease plasma biomarkers: the impact of blood collection tubes supplemented with protease inhibitors. Alzheimers Dement. 2024;20(S2). doi:10.1002/alz.088796.

11.   Figdore DJ, Schuder BJ, Ashrafzadeh-Kian S, Gronquist T, Bornhorst JA. Algeciras-Schimnich A. Differences in Alzheimer’s disease blood biomarker stability: Implications for the use of tau/amyloid ratios. Alzheimers Dement. 2025;21(4). doi:10.1002/alz.70173.

12.   Sunde AL, Alsnes IV, Aarsland D, et al. Preanalytical stability of plasma biomarkers for Alzheimer's disease pathology. Alzheimers Dement (Amst). 2023;15(2):e12439. doi:10.1002/dad2.12439. 

13.  Gaugler JE, Ascher-Svanum H, Roth DL, et al. Characteristics of patients misdiagnosed with Alzheimer's disease and their medication use: an analysis of the NACC-UDS database. BMC Geriatr. 2013;13:137. doi:10.1186/1471-2318-13-137. 

14.  Bomasang-Layno E, Bronsther R. Diagnosis and treatment of Alzheimer's disease:: An update. Dela J Public Health. 2021;7(4):74-85. doi:10.32481/djph.2021.09.009. 

15.  The psychological and emotional impact of dementia. Alzheimer’s Society. Updated June 27, 2022. Accessed September 23, 2025. https://www.alzheimers.org.uk/get-support/help-dementia-care/understanding-supporting-person-dementia-psychological-emotional-impact#:~:text=Impact%20of%20a%20dementia%20diagnosis,if%20the%20time%20feels%20right.

16.  Verberk IMW, Misdorp EO, Koelewijn J, et al. Characterization of pre-analytical sample handling effects on a panel of Alzheimer's disease-related blood-based biomarkers: Results from the Standardization of Alzheimer's Blood Biomarkers (SABB) working group. Alzheimers Dement. 2022;18(8):1484-1497. doi:10.1002/alz.12510.