• Howard A Fink, Eric J Linskens, Pombie C Silverman, J Riley McCarten, Laura S Hemmy, Jeannine M Ouellette, Nancy L Greer, Timothy J Wilt, and Mary Butler.
• Minneapolis VA Health Care System and University of Minnesota, Minneapolis, Minnesota (H.A.F., J.R.M., L.S.H., T.J.W.).
• Ann. Intern. Med. 2020 May 19; 172 (10): 669-677.

BackgroundBiomarker accuracy for Alzheimer disease (AD) is uncertain.PurposeTo summarize evidence on biomarker accuracy for classifying AD in older adults with dementia.Data SourcesElectronic bibliographic databases (searched from January 2012 to November 2019 for brain imaging and cerebrospinal fluid [CSF] tests and from inception to November 2019 for blood tests), ClinicalTrials.gov (to November 2019), and systematic review bibliographies.Study SelectionEnglish-language studies evaluating the accuracy of brain imaging, CSF testing, or blood tests for distinguishing neuropathologically defined AD from non-AD among older adults with dementia. Studies with low or medium risk of bias were analyzed.Data ExtractionTwo reviewers rated risk of bias. One extracted data; the other verified accuracy.Data SynthesisFifteen brain imaging studies and 9 CSF studies met analysis criteria. Median sensitivity and specificity, respectively, were 0.91 and 0.92 for amyloid positron emission tomography (PET), 0.89 and 0.74 for 18F-labeled fluorodeoxyglucose (18F-FDG) PET, 0.64 and 0.83 for single-photon emission computed tomography, and 0.91 and 0.89 for medial temporal lobe atrophy on magnetic resonance imaging (MRI). Individual CSF biomarkers and ratios had moderate sensitivity (range, 0.62 to 0.83) and specificity (range, 0.53 to 0.69); in the few direct comparisons, β-amyloid 42 (Aβ42)/phosphorylated tau (p-tau) ratio, total tau (t-tau)/Aβ42 ratio, and p-tau appeared more accurate than Aβ42 and t-tau alone. Single studies suggested that amyloid PET, 18F-FDG PET, and CSF test combinations may add accuracy to clinical evaluation.LimitationsStudies were small, biomarker cut points and neuropathologic AD were inconsistently defined, and methods with uncertain applicability to typical clinical settings were used. Few studies directly compared biomarkers, assessed test combinations, evaluated whether biomarkers improved classification accuracy when added to clinical evaluation, or reported harms.ConclusionIn methodologically heterogeneous studies of uncertain applicability to typical clinical settings, amyloid PET, 18F-FDG PET, and MRI were highly sensitive for neuropathologic AD. Amyloid PET, 18F-FDG PET, and CSF test combinations may add accuracy to clinical evaluation.Primary Funding SourceAgency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).

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