Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile
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 ind...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2021-07-01
|
Series: | Alzheimer’s Research & Therapy |
Subjects: | |
Online Access: | https://doi.org/10.1186/s13195-021-00863-y |
id |
doaj-f6f174b37dfb419b9a0109faee06b961 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 for the ALFA study |
spellingShingle |
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 for the ALFA study Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile Alzheimer’s Research & Therapy Preclinical Alzheimer’s disease CSF Biomarkers Subthreshold Cognitively unimpaired |
author_facet |
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 for the ALFA study |
author_sort |
Marta Milà-Alomà |
title |
Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile |
title_short |
Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile |
title_full |
Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile |
title_fullStr |
Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile |
title_full_unstemmed |
Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile |
title_sort |
cognitively unimpaired individuals with a low burden of aβ pathology have a distinct csf biomarker profile |
publisher |
BMC |
series |
Alzheimer’s Research & Therapy |
issn |
1758-9193 |
publishDate |
2021-07-01 |
description |
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 |
topic |
Preclinical Alzheimer’s disease CSF Biomarkers Subthreshold Cognitively unimpaired |
url |
https://doi.org/10.1186/s13195-021-00863-y |
work_keys_str_mv |
AT martamilaaloma cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT mahnazshekari cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT gemmasalvado cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT juandomingogispert cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT eidermarenazaurquijo cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT gregoryoperto cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT carlesfalcon cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT nataliavilortejedor cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT oriolgraurivera cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT aleixsalavila cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT gonzalosanchezbenavides cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT josemariagonzalezdeechavarri cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT carolinaminguillon cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT karinefauria cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT aidaninerolabaizan cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT andresperissinotti cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT marylinesimon cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT gwendlynkollmorgen cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT henrikzetterberg cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT kajblennow cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT marcsuarezcalvet cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT joseluismolinuevo cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile AT forthealfastudy cognitivelyunimpairedindividualswithalowburdenofabpathologyhaveadistinctcsfbiomarkerprofile |
_version_ |
1721245621584658432 |
spelling |
doaj-f6f174b37dfb419b9a0109faee06b9612021-08-01T11:43:34ZengBMCAlzheimer’s Research & Therapy1758-91932021-07-0113111210.1186/s13195-021-00863-yCognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profileMarta Milà-Alomà0Mahnaz Shekari1Gemma Salvadó2Juan Domingo Gispert3Eider M. Arenaza-Urquijo4Grégory Operto5Carles Falcon6Natalia Vilor-Tejedor7Oriol Grau-Rivera8Aleix Sala-Vila9Gonzalo Sánchez-Benavides10José Maria González-de-Echávarri11Carolina Minguillon12Karine Fauria13Aida Niñerola-Baizán14Andrés Perissinotti15Maryline Simon16Gwendlyn Kollmorgen17Henrik Zetterberg18Kaj Blennow19Marc Suárez-Calvet20José Luis Molinuevo21for the ALFA studyBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationCentro de Investigación Biomédica en Red Bioingeniería, Biomateriales y NanomedicinaCentro de Investigación Biomédica en Red Bioingeniería, Biomateriales y NanomedicinaRoche Diagnostics International Ltd.Roche Diagnostics GmbHDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of GothenburgDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of GothenburgBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationAbstract 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 NCT02485730https://doi.org/10.1186/s13195-021-00863-yPreclinicalAlzheimer’s diseaseCSFBiomarkersSubthresholdCognitively unimpaired |