Abstract
Failures in Alzheimer's disease (AD) drug trials highlight the need to further explore disease mechanisms and alterations of biomarkers during the development of AD. Using cross‐sectional data from 377 participants in the BioFINDER study, we examined seven cerebrospinal fluid (CSF) and six plasma biomarkers in relation to β‐amyloid (Aβ) PET uptake to understand their evolution during AD. In CSF, Aβ42 changed first, closely followed by Aβ42/Aβ40, phosphorylated‐tau (P‐tau), and total‐tau (T‐tau). CSF neurogranin, YKL‐40, and neurofilament light increased after the point of Aβ PET positivity. The findings were replicated using Aβ42, Aβ40, P‐tau, and T‐tau assays from five different manufacturers. Changes were seen approximately simultaneously for CSF and plasma biomarkers. Overall, plasma biomarkers had smaller dynamic ranges, except for CSF and plasma P‐tau which were similar. In conclusion, using state‐of‐the‐art biomarkers, we identified the first changes in Aβ, closely followed by soluble tau. Only after Aβ PET became abnormal, biomarkers of neuroinflammation, synaptic dysfunction, and neurodegeneration were altered. These findings lend in vivo support of the amyloid cascade hypotheses in humans.
Highlights
Continued failures in clinical trials for Alzheimer’s disease (AD) against presumably the correct drug targets highlight the need for further research to understand all important mechanisms and at what stage they occur and become measurable (Honig et al, 2018; Jack et al, 2018; Egan et al, 2019; Knopman, 2019; Selkoe, 2019)
In this study of 377 individuals who were cognitively unimpaired (n = 242) or had mild cognitive impairment (MCI) (n = 135), we examined 7 cerebrospinal fluid (CSF) and 6 plasma biomarkers in relation to fibrillar accumulation of bamyloid (Ab) accumulation to understand their evolution during the development of AD prior to the onset of dementia
In CSF, we found that the first significant changes were seen in Ab42, followed closely by P-tau and T-tau
Summary
Continued failures in clinical trials for Alzheimer’s disease (AD) against presumably the correct drug targets highlight the need for further research to understand all important mechanisms and at what stage they occur and become measurable (Honig et al, 2018; Jack et al, 2018; Egan et al, 2019; Knopman, 2019; Selkoe, 2019). Especially in the earlier stages of AD, would allow us to better understand the pathogenesis of the disease, which is essential for identifying potential drug targets, designing clinical trials, and improving diagnostics and the clinical work-up of AD (Blennow et al, 2010).
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