Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 12, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201911170
Keywords
Alzheimer disease; amyloid positron emission tomography; cerebrospinal fluid biomarkers; plasma biomarkers
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Funding
- European Research Council
- Swedish Research Council
- Knut and Alice Wallenberg foundation
- Marianne and Marcus Wallenberg foundation
- Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University
- Swedish Alzheimer Association
- Swedish Brain Foundation
- Parkinson foundation of Sweden
- Parkinson Research Foundation
- Skane University Hospital Foundation
- Swedish federal government under the ALF agreement
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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 beta-amyloid (A beta) PET uptake to understand their evolution during AD. In CSF, A beta 42 changed first, closely followed by A beta 42/A beta 40, phosphorylated-tau (P-tau), and total-tau (T-tau). CSF neurogranin, YKL-40, and neurofilament light increased after the point of A beta PET positivity. The findings were replicated using A beta 42, A beta 40, 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 A beta, closely followed by soluble tau. Only after A beta 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.
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