By Setting Standards, Experts Aim to Tame a Wild West of AD Blood Tests

Series - Alzheimer's Association International Conference (AAIC) 2024:

Mass spectrometry tests, immunoassays, Aβ42/40, various p-taus, their ratios … the number of blood tests for amyloid pathology in the last seven years has blossomed into a hopeful but confusing mess. Some are CLIA-certified—meaning the tests perform as claimed—but as yet, none are approved by the U.S. Food and Drug Administration or any other regulatory agency. How’s a primary care physician or neurologist to choose?

“It has been a Wild West for AD blood tests,” said Suzanne Schindler, Washington University, St. Louis. “That has brought significant risk,” she added. “If clinicians start using these tests and some perform poorly, this can diminish trust in all these biomarkers.” At AAIC last month in Philadelphia, Schindler argued that performance standards are necessary to help ensure accurate and timely diagnosis of Alzheimer’s disease as these tests leave the confines of AD research clinics and start to enter routine clinical care. Schindler co-wrote a Consensus Statement article on the topic in the July 2024 Nature Reviews Neurology with Oskar Hansson, Lund University, Sweden, and a panel of experts.

The good news is that several immunoassays and mass spec tests for amyloid can meet these standards. The twist? Test accuracy depends on the patient’s pretest likelihood of having amyloid pathology. If that sounds circular, read on …

Performance Standards: Check
Getting a timely diagnosis has become ever more urgent with the rollouts of lecanemab and donanemab. Anticipating these approvals, the Global CEO Initiative in 2022 convened a blood biomarker (BBM) workgroup to develop minimum performance standards for amyloid pathology tests. Co-lead by Schindler and Hansson, the group included dementia biomarker specialists, clinicians, and stakeholders from academia, industry, private foundations, and advocacy groups. Companies that sell AD BBMs or immunotherapies are in it, including Biogen, Cambridge, Massachusetts; Biomarkable BV, Gent, Belgium; C2N Diagnostics, St. Louis; Eisai Inc., Nutley, New Jersey; Eli Lilly, Indianapolis; Prothena Biosciences Inc., Brisbane, California; Quanterix Corporation, Billerica, Massachusetts, and Roche, Basel, Switzerland. “The Global CEOi brought people together who don’t normally talk to each other,” Schindler told Alzforum. “They got everyone to agree.”

Agree to what? Here’s where the detail comes in. The consensus performance recommendations the workgroup issued depend on the reason a given test will be used. For example, to confirm a suspected diagnosis of AD, the recommendations stipulate that the test should perform as well as approved tests of cerebrospinal fluid, namely having a specificity and a sensitivity of 90 percent. For a triage test, aka a test that will be confirmed with follow-up amyloid PET or CSF analysis, the sensitivity should still be 90 percent. As for its specificity, greater than 85 percent would suffice in primary care. For secondary care, that specificity could be even less stringent, at 75 percent, depending on what further testing is available (table below).

The paper goes into considerable depth explaining how specificity, sensitivity, positive and negative predictive values, and area under the curve are calculated and what they mean.

Context Matters. This performance matrix for secondary and primary care shows that even when a test surpasses the minimum acceptable performance, its positive and negative predictive values (PPV, NPV) depend on how prevalent amyloid pathology is in the patient’s age bracket. [Courtesy of Schindler et al., 2024.]

Cutoffs: Check
Those numbers, in turn, depend on cutoff values used to distinguish positive from negative test results. Cutoffs are tricky business. Set them too high, and there will be many false negatives, meaning delays in care or misdiagnoses. Set them too low, and there will be many false positives, a grave mistake.

Even when the cutoff is “just right,” some results come awfully close to the line, creating uncertainty. For this reason, the workgroup opted for two cutoffs. Values above the upper one indicate a positive test with high certainty, those beneath the lower would almost certainly be negative, and anything in between would need clarification via PET or CSF. This approach has already improved accuracy in dementia centers and in primary and secondary care research cohorts (Nov 2023 news; Part 1 of this series). No more than 15 to 20 percent of results should land in this “gray” zone. The Global CEOi workgroup reported that around that number of CSF test results do.

Additionally, in most medical testing, a test’s positive and negative predictive values depend on the prevalence of the tested condition in the population at hand. For AD, this means that among 80-year-olds who are cognitively impaired, a positive test is much more likely to be a true positive than in a 60-year-old who occasionally forgets where the car keys are. “Many people think that a test will give the answer they are looking for, but for that you have to have a high pretest probability of being amyloid-positive, because prevalence affects interpretation of the results,” cautioned Schindler. The lower a population’s pretest likelihood of amyloid pathology, the higher the specificity of the test itself needs to be for a positive result to be true. Ergo, both the test’s specificity and amyloid prevalence should inform interpretation of a given person’s results.

Where does all this leave the primary care physician who may not be fluent in biomarker stats? Schindler thinks that depends on the physician. “There is a lot of information out there on how to understand the accuracy of tests,” she said. Other common lab tests work similarly. Metabolic panels use patient age and sex to estimate their glomerular filtration rate from blood creatinine level. Cholesterol, lipoprotein, and triglyceride levels are used to calculate cardiovascular disease risk scores. “It may not be much of a reach that we could do something similar for amyloid testing,” said Schindler.

Still, it might help if the predictive value was calculated for physicians. To that end, Schindler has created an app that calculates PPVs and NPVs based on a patient’s age, MMSE score, and the given test’s specificity and sensitivity. The consensus statement also provides guidance for interpretation of test results in primary and secondary care (table below).

Guiding Interpretation. In primary (top) and secondary care (bottom), a person’s pretest likelihood of having AD, and the test’s accuracy, together determine its predictive values and how it should be read. [Courtesy of Schindler et al., 2024.]

For people whose pretest likelihood of having brain amyloid is high, a test with 90 percent specificity would have extremely high predictive value. In fact, Schindler has started patients on lecanemab who have both very high scores on the Precivity AD2 test and a very consistent clinical picture of AD, even without a follow-up CSF test or PET scan. “Many people don’t realize the current CSF test for amyloid pathology only has about 90 percent specificity and sensitivity,” she said. “If you are using a high-performing blood test, then it makes no sense to do a follow-up CSF. Essentially, that would mean running a lower-performing CSF test that carries some risk from a lumbar puncture.”

Which blood tests should clinicians be using? The consensus statement focused squarely on standards any candidate test should meet. It does not recommend specific tests. To date, the different tests currently being sold have been evaluated largely in separate cohorts and by different academic and commercial research groups. To guide clinicians in their choice, then, direct comparisons are in order. For AAIC news on those, see next story.—Tom Fagan

Comments

  1. This offers recommendations for the acceptable performance of blood biomarkers that predict abnormally high levels of cerebral amyloid plaques.

    I note a few key points:

    ▶ The recommended specificities and sensitivities are only for this intended use—to identify individuals with an abnormally high amyloid load, regardless of their current or future symptoms, and using amyloid PET (and possibly CSF) as the reference standard. The specificity and sensitivity of a biomarker will vary significantly depending on its intended use. For example, the 18F-florbetapir PET scan predicts neuritic Aβ plaques abnormal level at autopsy with 92 percent sensitivity and 100 percent specificity (Clark et al., 2012), while it predicts MCI patients who will develop AD dementia clinical symptoms with 67 percent sensitivity and 71 percent specificity, suggesting that 18F-florbetapir PET scans cannot be recommended for routine use in clinical practice to predict the progression from MCI to AD dementia (Martinez et al., 2017). 

    ▶ When Schindler et al. reference a confirmatory test, it should be understood as a test to confirm an abnormally high level of cerebral amyloid plaques, not as a test to predict clinical conversion to AD dementia symptoms or to diagnose AD. This is clearly outlined in the FDA dossier for 18F-florbetapir (202008Orig1s000) or the FDA De Novo dossier for the Lumipulse G Aβ42/40 ratio CSF test (DEN200072).

    ▶ In the context of initiating a treatment with significant side effects aimed at slowing the onset of AD dementia symptoms, blood tests predicting which patients would convert to AD dementia symptoms might be desirable. In this context, specificity should be preferred over sensitivity to avoid overdiagnosing individuals who will not develop symptoms of AD dementia, thus sparing them from side effects with little or no clinical benefit.

    In conclusion, when discussing the specificity and sensitivity of a blood biomarker for Alzheimer's disease, it is crucial to understand the intended use. The performance of the same blood biomarker will vary significantly based on its intended use, whether it's predicting patients with abnormally high levels of cerebral amyloid plaques or identifying pre-demented patients who will develop clinical symptoms of Alzheimer's dementia.

    References:

    FDA 202008Orig1s000, summary review for regulatory action, F18-florbetapir. CENTER FOR DRUG EVALUATION AND RESEARCH

    FDA DEN200072, decision summary, evaluation of automatic class II designation for Lumipulse G 13-Amyloid Ratio (1-42/1-40). EVALUATION OF AUTOMATIC CLASS Ill DESIGNATION FOR Lumipulse G 13-Amyloid Ratio (1-42/1-40) DECISION SUMMARY

    Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, Fleisher AS, Reiman EM, Sabbagh MN, Sadowsky CH, Schneider JA, Arora A, Carpenter AP, Flitter ML, Joshi AD, Krautkramer MJ, Lu M, Mintun MA, Skovronsky DM, . Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 2012 Aug;11(8):669-78. PubMed.

    Martínez G, Vernooij RW, Fuentes Padilla P, Zamora J, Bonfill Cosp X, Flicker L. 18F PET with florbetapir for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2017 Nov 22;11:CD012216. PubMed.

    View all comments by Jérôme Braudeau

  2. Dr. Braudeau is correct that the performance of blood biomarkers may vary in cognitively impaired and cognitively unimpaired groups. However, this paper only considers use of blood biomarkers in determining the presence/absence of amyloid pathology in patients who are cognitively impaired at the time of the test. We did not consider cognitively unimpaired individuals in these recommendations.

    View all comments by Suzanne Schindler

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References

News Citations

  1. Plasma p-Tau-217 Assays Work Well, But No Home Run for Diagnosis
  2. Are Alzheimer’s Blood Tests Ready for Primary Care?
  3. In Head-to-Head Testing, P-Tau217/Tau217 Comes Out on Top. By a Hair.

External Citations

  1. app

Further Reading

No Available Further Reading

Primary Papers

  1. Schindler SE, Galasko D, Pereira AC, Rabinovici GD, Salloway S, Suárez-Calvet M, Khachaturian AS, Mielke MM, Udeh-Momoh C, Weiss J, Batrla R, Bozeat S, Dwyer JR, Holzapfel D, Jones DR, Murray JF, Partrick KA, Scholler E, Vradenburg G, Young D, Algeciras-Schimnich A, Aubrecht J, Braunstein JB, Hendrix J, Hu YH, Mattke S, Monane M, Reilly D, Somers E, Teunissen CE, Shobin E, Vanderstichele H, Weiner MW, Wilson D, Hansson O. Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease. Nat Rev Neurol. 2024 Jul;20(7):426-439. Epub 2024 Jun 12 PubMed.

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