Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

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.

Clinical Utility of the Pathogenesis-related Proteins in Alzheimer’s Disease

“…Many findings provide in vivo support of the amyloid cascade hypotheses in humans [6]. Aβ42 caused the Cortex atrophy [13].…”

“…However, much evidence still confirms that the Aβ appears to be the initial disease mechanism in AD. Among initially amyloid-negative adults, Farrell found a regionally specific association between declining episodic memory and increased amyloid accumulation across multiple posterior cortical regions [5][6].…”

“…In the event of failure of clinical trials, Knopman [1] considered the selection of a population with positive Aβ to be too late for maximum treatment effect. Bischol [7] and Palmqvist [6] have proposed a potential solution for enrolling subjects with threshold amyloidosis. From experience, defining the threshold is very difficult.…”

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course—a joint PhD student course at University College London and University of Gothenburg

“…Plasma t-tau was also found to be increased in AD, though this is not correlated with CSF [31,32]. Promising results now exist for plasma p-tau, measured using a sensitive immunoassay with electrochemiluminescence detection and showing strong association with tau PET, as well as high concordance with CSF p-tau in a recent study by Palmqvist et al [33,34]. Several large replication studies, showing robust correlations with CSF p-tau and amyloid PET results, were presented during Alzheimer's Association International Conference 2019 (AAIC) but have not yet been published.…”

Choroid plexus APP regulates adult brain proliferation and animal behavior

“…al, 2019). A clinically accepted CSF biomarker is the amount of Aβ42 relative to Aβ40 (Palmqvist et al, 2019;Molinuevo et al, 2018), both of which are peptide metabolites of the amyloid precursor protein (APP). As Aβ42 oligomerizes and forms amyloid plaques in the parenchyma, an inverse amount of soluble Aβ42 is cleared into the CSF.…”