Cognitively unimpaired individuals with a low burden of A\u03b2 pathology have a distinct CSF biomarker profile

Marta Milà‐Alomà ,Grégory Operto,Andrés Perissinotti,Gemma Salvadó,Natàlia Vilor‐Tejedor ,Mahnaz Shekari,Karine Fauria,Maryline Simon,Oriol Grau‐Rivera ,Gwendlyn Kollmorgen,Carles Falcón ,Aida Niñerola‐Baizán ,José María González‐De‐Echávarri ,Juan Domingo Gispert,Kaj Blennow,Carolina Minguillón ,Gonzalo Sánchez‐Benavides ,Eider M Arenaza‐Urquijo ,Aleix Sala‐Vila ,Henrik Zetterberg,Marc Suárez‐Calvet ,José Luís Molinuevo

doi:10.1186/s13195-021-00863-y

Abstract

BackgroundUnderstanding 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.MethodsCross-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.ResultsThe 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.ConclusionsThere 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 registrationNCT02485730

Highlights

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
Amyloid-β 42 (Aβ42) [24], amyloid-β 40 (Aβ40), neurofilament light (NfL), neurogranin, soluble triggering receptor expressed on myeloid cells 2, chitinase-3-like protein 1 (YKL40), glial fibrillary acidic protein (GFAP), and α-synuclein were measured with the prototype NeuroToolKit (Roche Diagnostics International Ltd.) on a cobas e 411 instrument
S100 calcium-binding protein B, sTREM2 soluble triggering receptor expressed on myeloid cells 2 (TREM2), GFAP glial fibrillary acidic protein, Interleukin 6 (IL6) interleukin 6, Visual read (VR) visual read, YKL40 Chitinase-3-like protein 1 *In definition 2, we included 313 participants because 2 participants did not have Aβ positron emission tomography (PET) visual read assessment available and 3 additional participants had a discrepant cerebrospinal fluid (CSF) and visual read assessment

Summary

Introduction

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. Alzheimer’s disease (AD) has an initial preclinical stage characterized by brain deposits of amyloid-β (Aβ) and tau, without clinical manifestations [1,2,3,4,5]. Other pathophysiological processes occur in this preclinical stage, including microglial activation, synaptic dysfunction, neuronal injury, and vascular dysfunction [6,7,8]. All these processes can occur years or even decades before the onset of the first symptoms [5, 9, 10]. The thresholds for diagnostic classification may not be optimal to detect subtle Aβ pathology in Aβ- individuals [11]

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