Background: Amyloid-β positron emission tomography (PET) allows for in vivo detection of fibrillar amyloid plaques, a pathologic hallmark of Alzheimer's disease (AD). However, amyloid-β PET interpretation is limited by the imperfect correlation between PET and autopsy, and the fact that it is positive in about 20% to 30% of cognitively normal individuals and non-AD dementias, especially when older or carrying the ε4 allele of apolipoprotein E (ApoE4). When facing a positive amyloid PET, clinicians have to evaluate the probability of a pathologic false positive as well as the probability of amyloid positivity being age-related, comorbid to a primary non-AD dementia (clinicopathologic false positive). These probabilities can be calculated to reach an evidence-based interpretation of amyloid-β. As literature review and calculations cannot be easily performed in the day-to-day clinic, we propose a clinician friendly, evidence-based Bayesian approach to the interpretation of amyloid-β PET results in the differential diagnosis of patients with cognitive impairment.
Methods: We defined AD as a clinicopathologic entity in which amyloid-β is the primary cause of cognitive impairment. We systematically reviewed the literature to estimate the sensitivity and specificity of amyloid-β PET against neuropathologic examination. We inferred rates of clinicopathologic false positivity (non-AD dementia with comorbid amyloid) based on age-dependent and ApoE-dependent prevalence of amyloid positivity in normal individuals and AD patients provided in large meta-analyses published by the Amyloid Biomarker Study Group. We calculated positive predictive value (PPV) and negative predictive value (NPV) of amyloid-β PET, which are presented in a clinician-friendly table.
Results: PPV of PET is highest in young ApoE4- patients with high pre-PET probability of AD. In older ApoE4+ patients with low pre-PET probability of AD, positive amyloid-β PET scans must be interpreted with caution. A negative amyloid-β PET makes a diagnosis of AD unlikely except in old patients with high pre-PET probability of AD.
Conclusion: This evidence-based approach might provide guidance to clinicians and nuclear medicine physicians to interpret amyloid-β PET results for early and differential diagnosis of patients with progressive cognitive impairment.