CSF Aβ38 levels are associated with Alzheimer-related decline: implications for γ-secretase modulators

Nc, Cullen; Bateman, Randall J.; Palmqvist, Sebastian; Stomrud, Erik; Mattsson‐Carlgren, Niklas; Hansson, Oskar

doi:10.1101/2021.01.31.21250702

Cited by 2 publications

(1 citation statement)

References 32 publications

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“…Nevertheless, a metaanalysis pointed no signi cant difference in Aβ 1-38 levels between AD individuals and control group after comparing eight studies (34). Cullen and colleagues more recently demonstrated that higher CSF Aβ 1-38 levels are negatively associated with cognitive decline and risk of developing AD (35). In this context, it is evident that the potential of this isoform to add information in the preclinical stage of the disease remains under-explored.…”

Section: Discussionmentioning

confidence: 99%

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

Povala¹,

Bellaver²,

Bastiani³

et al. 2021

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Povala¹,

Bellaver²,

Bastiani³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

Soluble amyloid-beta isoforms predict downstream Alzheimer’s disease pathology

et al. 2021

View full text Add to dashboard Cite

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 model. 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 Aβ 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.

show abstract

CSF Aβ38 levels are associated with Alzheimer-related decline: implications for γ-secretase modulators

Cited by 2 publications

References 32 publications

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

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

Soluble amyloid-beta isoforms predict downstream Alzheimer’s disease pathology

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