Amyloid biomarkers: pushing the limits of early detection.

Abstract

This scientific commentary refers to ‘Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography’, by Palmqvist et al. (doi:10.1093/brain/aww015). One of the major advances in Alzheimer’s disease clinical research over the past two decades has been the development and validation of biomarkers for amyloid plaques and neurofibrillary tangles, the core neuropathological lesions that define the disease. Amyloid plaque deposition can be detected in vivo based on reductions in CSF levels of the amyloid-beta 1-42 amino acid polypeptide (amyloid-β1-42), or by PET imaging with radiotracers that bind selectively to the fibrillar aggregates of amyloid-β that form plaques (Blennow et al. , 2015). Collectively, amyloid-β biomarkers provide strong evidence for a prolonged ‘preclinical’ or ‘asymptomatic at-risk’ stage of Alzheimer’s disease, in which amyloid pathology is present in situ decades prior to the onset of clinical dementia (Sperling et al. , 2011). Even in the absence of overt cognitive deficits, normal individuals who have positive amyloid-β biomarkers show accelerated neurodegeneration and declining performance on neuropsychological tests compared to their amyloid-β-negative counterparts, and are at increased risk for developing incident cognitive impairment (Jagust, 2016). These observations have shifted the landscape of Alzheimer’s disease clinical research towards preclinical, biomarker-based detection of amyloid, and the implementation of early therapeutic interventions aimed at lowering amyloid and thus delaying or ultimately preventing the onset of clinical dementia (Sperling et al. , 2011). In this issue of Brain , Palmqvist and colleagues provide compelling evidence that CSF amyloid-β1-42 may be more sensitive than amyloid PET to the early stages of amyloid deposition (Palmqvist et al. , 2016), a finding that has important ramifications for our understanding of preclinical Alzheimer’s disease and for the design of prevention trials. Though they measure very different elements of amyloid biology, CSF amyloid-β1-42 and amyloid PET …