Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile

Marta Milà-Alomà, Mahnaz Shekari, Gemma Salvadó, Juan Domingo Gispert, Eider M. Arenaza-Urquijo, Grégory Operto, Carles Falcon, Natalia Vilor-Tejedor, Oriol Grau-Rivera, Aleix Sala-Vila, Gonzalo Sánchez-Benavides, José Maria González-de-Echávarri, Carolina Minguillon, Karine Fauria, Aida Niñerola-Baizán, Andrés Perissinotti, Maryline Simon, Gwendlyn Kollmorgen, Henrik Zetterberg, Kaj BlennowMarc Suárez-Calvet*, José Luis Molinuevo*

*Corresponding author for this work

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Abstract

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer’s continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile. Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [18F]-FDG, and [18F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20–40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex. Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2. Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials. Trial registration: NCT02485730

Original languageEnglish
Article number134
JournalAlzheimer's Research and Therapy
Volume13
Issue number1
DOIs
Publication statusPublished - 27 Jul 2021

Bibliographical note

Funding Information:
The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. JDG holds a “Ramón y Cajal” fellowship (RYC-2013-13054). EMA-U is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency (RYC2018-026053-I). NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation–Spanish State Research Agency. OG-R is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437), and receives funding from the Alzheimer’s Association Research Fellowship Program (2019-AARF-644568). ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at UCL. KB is supported by the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). MSC receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant agreement No. 948677). MSC also receives funding from the Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I).

Funding Information:
This publication is part of the ALFA study (ALzheimer and FAmilies). The authors would like to express their most sincere gratitude to the ALFA project participants, without whom this research would have not been possible. The collaborators of the ALFA study are Annabella Beteta, Raffaele Cacciaglia, Alba Ca?as, Carme Deulofeu, Irene Cumplido, Ruth Dominguez, Maria Emilio, Sherezade Fuentes, Laura Hernandez, Gema Huesa, Jordi Huguet, Paula Marne, Tania Mench?n, Albina Polo, Sandra Pradas, Anna Soteras, and Marc Vilanova. The authors would like to thank GE Healthcare for kindly providing [18F]flutemetamol doses of ALFA+ participants. The authors thank Roche Diagnostics International Ltd. for providing the kits to measure CSF biomarkers. ELECSYS, COBAS, and COBAS E are the trademarks of F-Hoffman La-Roche, Ltd. The Elecsys ?-Amyloid (1-42) CSF immunoassay used is a robust prototype assay for research use and is not a commercially available IVD assay. The measuring range of the assay is 200 (lower technical limit)?1700 pg/ml (upper technical limit). The performance of the assay beyond the upper technical limit has not been formally established. Therefore, the use of values above the upper technical limit, which are provided based on an extrapolation of the calibration curve, is restricted to exploratory research purposes and is excluded for clinical decision making.

Publisher Copyright:
© 2021, The Author(s).

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