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 Blennow, Marc Suárez-Calvet, José Luis Molinuevo, ALFA study, 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 Blennow, Marc Suárez-Calvet, José Luis Molinuevo, ALFA study

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.

Keywords: Alzheimer’s disease; Biomarkers; CSF; Cognitively unimpaired; Preclinical; Subthreshold.

Conflict of interest statement

MS is a full-time employee of the Roche Diagnostics International Ltd. GK is a full-time employee of the Roche Diagnostics GmbH. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and is a co-founder of the Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers and is a co-founder of the Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. MSC has served as a consultant and at advisory boards for the Roche Diagnostics International Ltd. and has given lectures in symposia sponsored by the Roche Diagnostics, S.L.U, and Roche Farma, S.A. JLM is currently a full-time employee of H. Lundbeck A/S and priory has served as a consultant or at advisory boards for the following for-profit companies, or has given lectures in symposia sponsored by the following for-profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, and ProMIS Neurosciences. The other authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Comparison of CSF p-tau, t-tau, NfL, and neurogranin between Aβ groups. The boxplots depict the median (horizontal bar), interquartile range (IQR hinges), and 1.5 × IQR (whiskers). Group differences were assessed by a one-way analysis of covariance (ANCOVA) adjusted by age and sex, followed by Dunnett-corrected pairwise post hoc comparisons. We show the percentage of increase in the mean of each biomarker in the low burden group compared to the Aβ- group. The percentage is shown in bold if the difference is statistically significant. “Low burden” refers to “low burden of Aβ pathology”. NS, not significant. *P <0.05; **P <0.01; ***P <0.001; ****P <0.0001

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