Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-β positivity
Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer’s disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this...
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Published in: | Molecular psychiatry Vol. 26; no. 10; pp. 5864 - 5874 |
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Main Authors: | , , |
Format: | Journal Article Web Resource |
Language: | English |
Published: |
London
Nature Publishing Group UK
01-10-2021
Nature Publishing Group |
Subjects: | |
Online Access: | Get full text |
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Summary: | Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer’s disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-β
42
and [18F]Florbetapir PET assessments at baseline (
n
= 867) and at 2-year follow-up (
n
= 289). Longitudinal trajectories of amyloid-β positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (
n
= 289), we found that participants with normal CSF/PET amyloid-β biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (
χ
2
(1)
= 5.40;
p
< 0.05). Progression to CSF+/PET+ status was ten times more frequent in cases with discordant biomarkers, as compared to csf−/pet− cases (
χ
2
(1)
= 18.86;
p
< 0.001). Compared to the CSF+/pet− group, the csf−/PET+ group had lower
APOE
-ε4ε4 prevalence (
χ
2
(6)
= 197;
p
< 0.001;
n
= 867) and slower rate of brain amyloid-β accumulation (
F
(3,600)
= 12.76;
p
< 0.001;
n
= 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-β accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-β biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways (“CSF-first” vs. “PET-first”) toward established amyloid-β pathology, characterized by different genetic profiles and rates of amyloid-β accumulation. In conclusion, CSF and PET amyloid-β biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 scopus-id:2-s2.0-85097532229 |
ISSN: | 1359-4184 1476-5578 1476-5578 |
DOI: | 10.1038/s41380-020-00950-w |