Blood-Based Biomarkers for Alzheimer's Disease
The Role of p-tau217
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The diagnosis of Alzheimer's disease (AD) has evolved significantly, with a shift towards incorporating biomarkers for earlier and more accurate detection.[3] Traditionally, diagnosis relied on clinical symptoms, but this approach often suffered from poor correlation with postmortem neuropathological findings.[20] The development of blood-based biomarkers (BBMs) has emerged as a promising avenue for improving diagnostic accuracy, particularly due to their accessibility and cost-effectiveness compared to methods like cerebrospinal fluid (CSF) analysis or positron emission tomography (PET) imaging.[4]
Diagnostic Performance of Plasma %p-tau217
Among the various blood-based biomarkers, phosphorylated tau at threonine 217 (p-tau217) has shown significant promise as a marker of AD pathology.[1] P-tau217 has demonstrated superior performance compared to other p-tau isoforms, such as p-tau181, in terms of diagnostic accuracy and early prognosis.[1] Studies have shown that p-tau217 levels correlate strongly with amyloid-PET and tau-PET status, two reliable neuroimaging methods used to evaluate AD.[36] Furthermore, p-tau217 has been found to differentiate AD from other neurodegenerative diseases with high accuracy.[78]
A recent study published in Nature Medicine compared the diagnostic performance of plasma %p-tau217 (the ratio of phosphorylated tau at residue 217 to the concentration of non-phosphorylated mid-region tau) with clinically used and FDA-approved CSF assays (CSF Aβ42/40 and p-tau181/Aβ42) in independent Swedish and US cohorts.[54] The primary outcome was the detection of Aβ pathology as determined by Aβ PET imaging, and secondary outcomes included the classification of brain tau aggregates as determined by tau PET imaging and agreement with a clinical AD diagnosis.[54] The main analyses focused on individuals with cognitive impairment (MCI and mild dementia), which is the target population for available disease-modifying treatments.[54]
Clinical Implications
The study found that plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology.[54] In the cognitively impaired subcohorts, the positive predictive value (PPV) of plasma %p-tau217 was equivalent to the CSF tests, demonstrating that the blood test could confirm the presence of Aβ pathology as accurately as CSF tests.[54] The high performance of plasma %p-tau217 in classifying Aβ and tau PET status indicates that this BBM may be able to replace approved CSF and PET measures in the diagnostic workup of AD.[54]
Future Directions
The high accuracy of plasma %p-tau217 has significant implications for clinical practice. The use of high-performance blood tests can improve access to accurate AD diagnosis and AD-specific treatments.[54] In patients with MCI and mild dementia who may be candidates for anti-amyloid treatments, plasma %p-tau217 classified Aβ PET status with an accuracy, a PPV, and an NPV of approximately 90% when a standard approach using a single cutoff was applied.[54] The study suggests that, in community settings, AD blood biomarkers have the potential to rule out impending dementia over a 10-year period, assuming other risk factors remain stable.[1] This could help counsel individuals concerned about their cognitive health, providing reassurance about low dementia risk, enhancing psychosocial well-being, and reducing unnecessary healthcare interventions.[54]
Further research integrating multiple biomarkers and focusing on at-risk subgroups might help enhance early detection of dementia.[54] Tailoring biomarker-based strategies to individual clinical profiles will be crucial in optimizing counselling, care, and intervention in community settings.[54] Establishing a universal cut-point for p-tau181 or p-tau217 should be a priority in future studies of these biomarkers.[26]
Authoritative Sources
- Barthélemy, N. R., Li, Y., Joseph-Mathurin, N., Gordon, B. A., Hassenstab, J., Benzinger, T. L. S., Buckles, V., Fagan, A. M., Perrin, R. J., et al. A Soluble Phosphorylated Tau Signature Links Tau, Amyloid and the Evolution of Stages of Dominantly Inherited Alzheimer’s Disease. Nat. Med. 2020;26:398–407.↩
- McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s Disease. Neurology. 1984;34:939–944.↩
- Leuzy A, Janelidze S, Mattsson-Carlgren N, Palmqvist S, Jacobs D, Cicognola C, Stomrud E, Vanmechelen E, Dage JL, Hansson O. Comparing the Clinical Utility and Diagnostic Performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays. Neurology. 2021;97:e1681–e1694.↩
- Salvadó, G., Schindler, S. E., He, Y., Janelidze, S., Collij, L. E., Saef, B., Henson, R. L., Chen, C. D., Gordon, B. A., et al. Highly Accurate Blood Test for Alzheimer’s Disease Is Similar or Superior to Clinical Cerebrospinal Fluid Tests. Nat. Med. 2024;30:1085–1095.↩
- Hanes J, Kovac A, Kvartsberg H, Kontsekova E, Fialova L, Katina S, Kovacech B, Stevens E, Hort J, Vyhnalek M, et al. Evaluation of a Novel Immunoassay to Detect P-Tau Thr217 in the CSF to Distinguish Alzheimer Disease from Other Dementias. Neurology. 2020;95:e3026–e3035.↩
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