Soluble Amyloid-Beta Isoforms Predict Downstream Alzheimer’s Disease Pathology

Abstract

Background: Changes in soluble amyloid-beta (Aβ) levels in cerebrospinal fluid (CSF) are detectable at early preclinical stages of Alzheimer's disease (AD). However, whether Aβ levels can predict downstream AD pathological features in cognitively unimpaired (CU) individuals remains unclear. With this in mind, we aimed at investigating whether a combination of soluble Aβ isoforms can predict tau pathology (T+) and neurodegeneration (N+) positivity. Methods: We used CSF measurements of three soluble Aβ peptides (Aβ1‑38, Aβ1‑40 and Aβ1‑42) in CU individuals (n = 318) as input features in machine learning (ML) models aiming at predicting T+ and N+. Input data was used for building 2046 tuned predictive ML models with a nested cross-validation technique. Additionally, proteomics data was employed to investigate the functional enrichment of biological processes altered in T+ and N+ individuals. Results: Our findings indicate that Aβ isoforms can predict T+ and N+ with an area under the curve (AUC) of 0.929 and 0.936, respectively. Additionally, proteomics analysis identified 17 differentially expressed proteins (DEPs) in individuals wrongly classified by our ML algorithm. More specifically, enrichment analysis of gene ontology biological processes revealed an upregulation in myelinization and glucose metabolism-related processes in CU individuals wrongly predicted as T+. A significant enrichment of DEPs in pathways including biosynthesis of amino acids, glycolysis/gluconeogenesis, carbon metabolism, cell adhesion molecules and prion disease was also observed. Conclusions: Our results demonstrate that, by applying a refined ML analysis, a combination of Ab isoforms can predict T+ and N+ with a high AUC. CSF proteomics analysis highlighted a promising group of proteins that can be further explored for improving T+ and N+ prediction.

Development of fluorophores for the detection of oligomeric aggregates of amyloidogenic proteins found in neurodegenerative diseases

“…However, many of these tau probes have yet to be evaluated in biologically relevant samples such as brain tissue or biological fluids such as cerebrospinal fluid (CSF). Elevated levels of soluble aggregates of amyloidogenic proteins in CSF have been reported in patients with AD, therefore the detection of endogenous levels of these aggregates in CSF may complement AD diagnosis as a less invasive avenue that can potentially allow for monitoring of AD progression (Blennow, 2004;De et al, 2019;Povala et al, 2021). The design of fluorescent probes that can detect oligomeric α-Synuclein are currently based on scaffolds that showed promise as a probe for detecting Lewy bodies and neurites and have been limited to experiments in vitro.…”