Abstract
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-β42 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 (χ2(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 (χ2(1) = 18.86; p < 0.001). Compared to the CSF+/pet− group, the csf−/PET+ group had lower APOE-ε4ε4 prevalence (χ2(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.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.The abnormal deposition of amyloid-β into plaques is considered one of the earliest neuropathological events in Alzheimer’s disease
While it has been suggested that discordance in amyloid-β biomarkers might be related to measurement issues, due to different detection thresholds of CSF vs. PET techniques [13], recent studies have indicated that biomarker discordance might be biologically relevant, with each amyloid-β biomarker providing distinct information [15, 19, 35]
When examining the severity of neuropsychiatric depressive symptoms, we found that the Geriatric Depression Scale (GDS) score was significantly higher in the csf−/PET+ group (2.09 [2.07]), as compared to all remaining groups (F(3,857) = 2.75, p < 0.05) (Supplementary Table 4). (iii) Genetic assessment revealed a significant association between number of APOE-ε4 alleles and CSF/PET amyloid-β biomarkers profile (χ2(6) = 197; p < 0.001; Table 2)
Summary
Current research diagnostic criteria for Alzheimer’s disease promote the use of either CSF (low levels of CSF amyloid-β42) or PET imaging (high brain retention of amyloid-β PET tracers) as equivalent measures of amyloid-β pathology [1,2,3,4]. Amyloid-β PET and CSF amyloid-β42 usually provide highly concordant information, which has justified their interchangeable use in the diagnosis of Alzheimer’s disease dementia [5, 6]. While it has been suggested that discordance in amyloid-β biomarkers might be related to measurement issues, due to different detection thresholds of CSF vs PET techniques [13], recent studies have indicated that biomarker discordance might be biologically relevant, with each amyloid-β biomarker providing distinct information [15, 19, 35]. Amyloid-β PET is a direct measure of fibrillar amyloid-β deposition in the brain, as reported in antemortempostmortem correlative studies [37,38,39,40]
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