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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AgenT SAS
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.
Washington University
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.
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