Aptamarker prediction of brain amyloid-β status in cognitively normal individuals at risk for Alzheimer's disease

PLoS One. 2021 Jan 4;16(1):e0243902. doi: 10.1371/journal.pone.0243902. eCollection 2021.

Abstract

The traditional approach to biomarker discovery for any pathology has been through hypothesis-based research one candidate at a time. The objective of this study was to develop an agnostic approach for the simultaneous screening of plasma for consistent molecular differences between a group of individuals exhibiting a pathology and a group of healthy individuals. To achieve this, we focused on developing a predictive tool based on plasma for the amount of brain amyloid-β deposition as observed in PET scans. The accumulation of brain amyloid-β (Aβ) plaques is a key risk factor for the development of Alzheimer's disease. A contrast was established between cognitively normal individuals above the age of 70 that differed for the amount of brain amyloid-β observed in PET scans (INSIGHT study group). Positive selection was performed against a pool of plasma from individuals with high brain amyloid and negative selection against a pool of plasma from individuals with low brain amyloid This enriched, selected library was then applied to plasma samples from 11 individuals with high levels of brain amyloid and 11 individuals with low levels of brain Aβ accumulation. Each of these individually selected libraries was then characterized by next generation sequencing, and the relative frequency of 10,000 aptamer sequences that were observed in each selection was screened for ability to explain variation in brain amyloid using sparse partial least squares discriminant analysis. From this analysis a subset of 44 aptamers was defined, and the individual aptamers were synthesized. This subset was applied to plasma samples from 70 cognitively normal individuals all above the age of 70 that differed for brain amyloid deposition. 54 individuals were used as a training set, and 15 as a test set. Three of the 15 individuals in the test set were mis-classified resulting in an overall accuracy of 80% with 86% sensitivity and 75% specificity. The aptamers included in the subset serve directly as biomarkers, thus we have named them Aptamarkers. There are two potential applications of these results: extending the predictive capacity of these aptamers across a broader range of individuals, and/or using the individual aptamers to identify targets through covariance analysis and reverse omics approaches. We are currently expanding applications of the Aptamarker platform to other diseases and target matrices.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / diagnosis
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / blood*
  • Biomarkers / blood
  • Case-Control Studies
  • Early Diagnosis
  • Female
  • Humans
  • Male
  • SELEX Aptamer Technique*

Substances

  • Amyloid beta-Peptides
  • Biomarkers

Associated data

  • figshare/10.6084/m9.figshare.13363067.v2

Grants and funding

The study was funded wholly by NeoNeuro. During the course of this study, NeoNeuro was financially supported by NeoVentures Biotechnology Inc. GPenner received grant funding from GSK and has ownership over NeoNeuro. SLecocq and AChopin are employees of NeoNeuro. XVedoya has an ownership over NeoNeuro. SLista received lecture honoraria from Roche. AVergallo is an employee of Eisai Inc. He does not receive any fees or honoraria since November 2019. Before November 2019 he had he received lecture honoraria from Roche, MagQu LLC, and Servier. This work has been performed during his previous position at Sorbonne University, Paris, France. HHampel is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019; before May 2019 he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare and Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. This work has been performed during his previous position at Sorbonne University, Paris, France. At Sorbonne University he was supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherche sur Alzheimer”, Paris, France." GPenner and XVedoya privately own all shares in NeoVentures. The funders had a full role in the study design, and data analysis, decision to publish and preparation of this manuscript.