Editors' ChoiceAlzheimer’s Disease

Biomarker changes in early Alzheimer’s disease

+ See all authors and affiliations

Science Translational Medicine  03 Aug 2016:
Vol. 8, Issue 350, pp. 350ec123
DOI: 10.1126/scitranslmed.aah4510

A key first step in the pathogenesis of Alzheimer’s disease (AD) is deposition of β-amyloid (Aβ) insoluble plaques in the brain. Amyloid deposition begins 10 to 20 years before the development of neurofibrillary tangles, neuronal loss, and cognitive deficits. Amyloid deposition in humans has generally been assessed by the presence or absence of Aβ imaging of Pittsburgh compound B (PIB) by positron emission tomography (PET) scan, or by cerebrospinal fluid (CSF) concentration of Aβ42, the Aβ isoform most prone to form plaques. However, previous work in rodents found dynamic changes in Aβ during plaque formation, such as rapid clearance from interstitial fluid. Defining AD biomarkers on a more continuous scale may allow for more refined selection of participants for AD secondary prevention trials.

To establish how biomarkers for Aβ deposition change in preclinical AD, Vlassenko et al. analyzed cognitively normal older adults who had undergone longitudinal amyloid imaging with PIB. Participants were divided into three groups: stable PIB-negative, stable PIB-positive, and PIB converters who changed from amyloid-negative to amyloid-positive on serial PIB scans, suggestive of early preclinical AD. CSF from all participants was collected, and baseline Aβ42 concentrations were measured. PIB converters had lower baseline CSF Aβ42 concentrations than stable PIB-negative individuals but higher than PIB-positive individuals. The authors also noted that concentrations of CSF tau, a marker of neurofibrillary tangles and neuronal injury, were higher in stable PIB-positive participants than both stable PIB-negative and PIB converter participants. These findings suggest that CSF Aβ42 concentrations change dynamically in humans during AD pathogenesis and that biomarker profiles might allow for more refined definition of an individual’s stage in AD pathogenesis.

Recent efforts to find a treatment to prevent or delay AD have focused on initiating treatment trials during the asymptomatic, preclinical phase of the disease. Therefore, amyloid imaging and CSF biomarkers are considered key factors needed to define participants in clinical trials. Vlassenko et al. have extended findings from animal models to show that Aβ deposition in the brain is a dynamic process and can be captured using AD biomarkers in human patients. Because CSF was not available longitudinally in this study, further longitudinal studies will be needed to determine if CSF Aβ42 alone or in combination with other biomarkers (PIB, tau) may be able to establish an individual’s risk for progression to symptomatic AD. No participants in this study progressed to symptomatic AD; therefore, longer-term follow-up is needed to establish the clinical relevance of these biomarker changes.

A. G. Vlassenko et al., Imaging and cerebrospinal fluid biomarkers in early preclinical Alzheimer disease. Ann. Neurol. 10.1002/ana.24719 (2016). [Abstract]

Navigate This Article