Soluble amyloid-beta isoforms predict downstream Alzheimer's disease pathology.

TitleSoluble amyloid-beta isoforms predict downstream Alzheimer's disease pathology.
Publication TypeJournal Article
Year of Publication2021
AuthorsPovala G, Bellaver B, De Bastiani MAntônio, Brum WS, Ferreira PCL, Bieger A, Pascoal TA, Benedet AL, Souza DO, Araujo RM, Zatt B, Rosa-Neto P, Zimmer ER
Corporate Authorsfor the Alzheimer’s Disease Neuroimaging Initiative
JournalCell Biosci
Volume11
Issue1
Pagination204
Date Published2021 Dec 11
ISSN2045-3701
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 (Aβ, Aβ and Aβ) 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.

DOI10.1186/s13578-021-00712-3
Alternate JournalCell Biosci
PubMed ID34895338
PubMed Central IDPMC8665586
Grant List88882.345577/2019-01 / / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior /
88887.336490/2019-00 / / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior /
312410/2018-2 / / Conselho Nacional de Desenvolvimento Científico e Tecnológico /
435642/2018-9 / / Conselho Nacional de Desenvolvimento Científico e Tecnológico /
Serra-1912-31365 / / Instituto Serrapilheira /
30786.434.24734.23112017 / / Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul /
54392.632.30451.05032021 / / Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul /
MOP-11-51-31 / CAPMC / CIHR / Canada
FRN, 152985 / CAPMC / CIHR / Canada
NIRG-12-92090 / ALZ / Alzheimer's Association / United States
NIRP-12-259245 / ALZ / Alzheimer's Association / United States
2020-VICO-279314 / / Fonds de Recherche du Québec - Santé /