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Blood-based biomarkers have the potential to revolutionize clinical practice and clinical trials in Alzheimer disease (AD). However, to date, this “holy grail” opportunity has not been realized owing to a broad range of issues, including the lack of a clearly defined context of use (COU), lack of standardization of methods, and numerous failures at replication. Recently, however, a shift in the paradigm has occurred, with my colleagues and I proposing specific COUs for blood-based biomarkers along with potential paradigms for advancing from discovery to clinic and potential acceptable standards.1,2
One specific need that has emerged is the availability of a blood-based screening tool for use within the COU of primary care settings.2 Such a tool is not diagnostic, but rather, would be used as part of a multitiered diagnostic approach beginning with a blood test to determine which specific patients should be referred for additional confirmatory diagnostic procedures.1,2 The goal of such a test, as with all primary care screening tests, is to have a very high negative predictive power to rule out the large numbers of patients who do not need additional procedures and can be told “you’re okay, stop worrying.” The availability of such a tool may help the diagnostic process for clinical practice and clinical trials.
In this issue of JAMA Neurology, Palmqvist et al3 provide preliminary evidence for a test with the specific COU of screening for amyloid positivity, which the authors suggest may have utility in primary care settings. The authors examine plasma β-amyloid 40 (Aβ40), Aβ42, and the Aβ42/Aβ40 ratio using the Elecsys immunoassay system (Roche Diagnostics) in relation to cerebral amyloid status in a training cohort (513, cognitively unimpaired; 265, mild cognitive impairment; and 64, AD) with preliminary data from an independent small-scale replication (ie, validation) cohort (34, cognitively unimpaired; 109, mild cognitive impairment; and 94, AD). Plasma neurofilament light chain, tau, and neurofilament heavy chain were also examined in the training cohort and APOE genotype was entered into the models. Overall, the performance of the assay was excellent. Correlations between cerebrospinal fluid and plasma amyloid levels were low as in earlier work. There were statistically significant mean group differences between the amyloid-positive and amyloid-negative groups; however, as seen in the figures, there was substantial overlap for individual Aβ40, Aβ42, and the Aβ42/Aβ40 values. In the training cohort, the authors found an area under the curve of 0.77 for the Aβ42/Aβ40 ratio, but the use of Aβ40, Aβ42, and APOE increased the AUC to 0.85. When applied to the validation cohort, the Aβ42/Aβ40 ratio yielded a sensitivity of 0.70 and specificity of 0.73. If applied to the expected base rates found in a primary care setting (ie, 10%-12%), the negative predictive power would be greater than 0.90; however, the positive predictive power would be 0.22.
This work makes several significant advancements in the field. First, the study clearly sets the stage for a COU of a blood screen for amyloid positivity by this protocol design. Second, the use of a fully automated procedure yields performance measurements that are superior to many earlier nonautomated procedures. Third, the discovery findings in a training cohort were applied directly to a small test cohort with solid results. Together, this study suggests that the field is 1 step closer to the actual application of blood based biomarkers with specific COUs in AD.
These results certainly leave room for improvement. The primary concern is the scalability of the methods. International working groups (of which I have been a participant) have recently outlined the steps and considerations for taking AD blood biomarkers from discovery to clinic, with scalability a primary concern.1,2 If primary care physicians are to use such a technology, the technology must have the capacity to conduct hundreds of millions of assays annually around the globe. A primary barrier to the scalability of the technology presented here is the blood collection parameters. A blood test for primary care must fit into the existing protocols and parameters in clinical laboratory settings. The blood collection and processing procedures are not applicable to standard clinical lab practice and will cause substantial barriers to clinical application. Replication specifically within the intended population would be of tremendous value. Finally, there is a disconnect between the primary care emphasis COU and the study design, which was constructed for a blood test of amyloid positivity. The latter is of great use for clinical trials, but no currently available drugs for patient use target amyloid. Therefore, this specific COU is geared more toward clinical trial application than primary care physicians who currently need a test for the presence or absence of AD so currently available treatments and support can be put in place for patients and family members.
Overall, the findings of Palmqvist et al3 are promising and demonstrate that the field is rapidly moving from “if” blood biomarkers can be used in AD to “how” they can be used. This work demonstrates the superiority of automated technologies, and the findings provide a solid foundation on which to build. The COU of a blood screen for amyloid positivity could be of value to any new clinical trial and could save trial costs. In addition, if an antiamyloid drug becomes approved by regulatory agencies, such a test would be required to determine eligibility for the drug.
Corresponding Author: Sid E. O’Bryant, PhD, Institute for Translational Research, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Ft Worth, TX 76106 (firstname.lastname@example.org).
Published Online: June 24, 2019. doi:10.1001/jamaneurol.2019.0845
Conflict of Interest Disclosures: Dr O’Bryant reported grants from the National Institute on Aging during the conduct of the study and personal fees and other support from Roche outside the submitted work; had patent numbers 20160291036 and 20160154010 pending and licensed and patents pending for precision medicine tools for diagnosing and treating neurodegenerative diseases; has served on an Advisory Board for Roche Diagnostics; and is founding scientist of Cx Precision Medicine.
O’Bryant SE. Blood Biomarkers for Use in Alzheimer Disease—Moving From “If” to “How?”. JAMA Neurol. Published online June 24, 201976(9):1009–1010. doi:10.1001/jamaneurol.2019.0845
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