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ATN Profile: For and beyond Alzheimer’s disease

18 September 2024

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60%-70% of dementia cases.1 Blood-based biomarkers (BBMs) specific to AD pathology, such as beta-amyloid 42/40 and pTau217, are now available to clinicians. But this still leaves up to 40% of patients with clinical signs of mild cognitive impairment (MCI) or possible dementia without answers.

With new therapies available for AD, appropriate triaging of patients who need a neurologist for treatment and monitoring is critical. BBMs can help with that triaging process, and pTau217 has emerged as a lead candidate for a triaging tool. Indeed, a single biomarker with high sensitivity and specificity to rule-in patients likely of having AD is promising. However, using this marker alone leaves the other 30%-40% of patients, leaving clinicians with little else to go on.

When a patient with possible MCI or dementia first presents, the primary clinical question for the clinician is, “What is going on with this patient?” The question of whether a patient may have AD is a secondary clinical question, alongside questions regarding polypharmacy, vitamin deficiencies, hormonal imbalances or metabolic problems. Using pTau217 only addresses one of the many secondary clinical questions, making it a less effective clinical approach when compared to a BBM panel, which provides additional insight and evidence toward the primary clinical question.

This was the impetus behind Labcorp’s ATN Profile, which employs three well-studied BBMs in a single assay. Designed to help rule-in or rule-out evidence of AD pathology, the profile also provides additional biological evidence to help guide clinicians for those 30%-40% of patients who do not have AD. The three biomarkers in the ATN Profile are:

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Interpretation

Hampel et al10 published a review article summarizing how to interpret and understand the eight possible outcomes from an ATN-like test. Each assay within the ATN panel has a cutoff that provides an indication of whether a patient’s measured value is considered normal or abnormal. For NfL, cutoffs are based on age ranges recognizing that baseline measurable NfL levels increase with age.11 Each of the three assays is then given a “-” or “+” indicator corresponding to a normal or abnormal result, respectively. There are eight possible combinations of results, and these combinations group into three possible clinical interpretations: normal, AD continuum (“AD pathology” and “probable AD”) and non-AD pathology or neurodegenerative disease.

A normal result, where there is no evidence of disease, occurs when each of the three markers is negative: A-, T- and N-. Any result where A is positive indicates that the patient is on the AD continuum. If these patients are not already under the care of a neurologist, they are candidates for immediate referral, where these findings can then be confirmed and potential treatment options can be assessed. Any result where A is negative, but T and/or N are positive, indicates non-AD pathology or neurodegeneration. This additional set of A negative results provides significant value to a clinician trying to address the primary clinical question of what might be going on with the patient.

Clinical use for patient triaging

Based on the demonstrated performance of the plasma Aβ42/40 component of the ATN Profile, the assay meets the newly published recommendations for sensitivity (≥90.0%) and specificity (≥85.0%) for a triage test performed in a primary care setting.12 For neurologists familiar with the various markers and the type of information they convey about disease, pTau217 is a simple single marker likely to quickly become the default assay for assessing AD. However, in primary care settings, the ATN Profile has notable benefits over pTau217. Providing important clinical information about the patient’s health beyond just AD makes this a more useful assay for assessment and triage. In terms of interpretation, primary care physicians are no more acquainted with pTau217 than they are with any of the ATN Profile components. The results of the three biomarkers are summarized using language that abstracts the complexity of the individual biomarker results. Ultimately, the ATN Profile provides the physician with a clear summary of likely AD status and whether there is evidence of other non-AD pathologies that should be investigated.

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References

  1. Dementia. World Health Organization. March 15, 2023. Accessed August 19, 2024. https://www.who.int/news-room/fact-sheets/detail/dementia
  2. Ovod V, Ramsey KN, Mawuenyega KG, et al. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis [published correction appears in Alzheimers Dement. 2017 Oct;13(10):1185]. Alzheimers Dement. 2017;13(8):841-849. doi:10.1016/j.jalz.2017.06.2266
  3. Yamashita K, Miura M, Watanabe S, et al. Fully automated and highly specific plasma β-amyloid immunoassays predict β-amyloid status defined by amyloid positron emission tomography with high accuracy. Alzheimers Res Ther. 2022;14(1):86. doi:10.1186/s13195-022-01029-0
  4. Yamashita K, Watanabe S, Ishiki K, et al. Fully automated chemiluminescence enzyme immunoassays showing high correlation with immunoprecipitation mass spectrometry assays for β-amyloid (1-40) and (1-42) in plasma samples. Biochem Biophys Res Commun. 2021;576:22-26. doi:10.1016/j.bbrc.2021.08.066
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  6. Bun S, Ito D, Tezuka T, et al. Performance of plasma Aβ42/40, measured using a fully automated immunoassay, across a broad patient population in identifying amyloid status. Alzheimers Res Ther. 2023;15(1):149. doi:10.1186/s13195-023-01296-5
  7. Oberstein TJ, Schmidt MA, Florvaag A, et al. Amyloid-β levels and cognitive trajectories in non-demented pTau181-positive subjects without amyloidopathy. Brain. 2022;145(11):4032-4041. doi:10.1093/brain/awac297
  8. Jack CR. PART and SNAP. Acta Neuropathol. 2014;128(6):773-776. doi:10.1007/s00401-014-1362-3
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  10. Hampel H, Cummings J, Blennow K, Gao P, Jack CR, Vergallo A. Developing the ATX(N) classification for use across the Alzheimer disease continuum. Nat Rev Neurol. 2021;17(9):580-589. doi:10.1038/s41582-021-00520-w
  11. Khalil M, Pirpamer L, Hofer E, et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun. 2020;11(1):812. doi:10.1038/s41467-020-14612-6
  12. Schindler SE, Galasko D, Pereira AC, et al. Acceptable performance of blood biomarker tests of amyloid pathology — recommendations from the Global CEO Initiative on Alzheimer’s Disease. Nat Rev Neurol. 2024;20:426-439. doi:10.1038/s41582-024-00977-5