Emerging beta‐amyloid pathology is associated with tau, synaptic, neurodegeneration and gray matter volume differences

Abstract

AbstractBackgroundNew clinical trials, like the A3, are targeting participants with emerging amyloid pathology (between 20‐40 centiloids (CL). The aim of this study is to describe if there are detectable differences in tau, synaptic, inflammatory, neurodegeneration CSF markers and brain structure in participants with emerging amyloid pathology.MethodCSF Aß42, Aß40, t‐tau, p‐tau, neurogranin, GFAP, IL‐6, YKL‐40, sTREM2, NfL, S100B and α‐synuclein were measured with Elecsys® CSF assays and the Roche NeuroToolKit robust prototype assays in 303 cognitively unimpaired participants of the ALFA+ cohort. Participants also underwent APOE genotyping, structural MRI, as well as [18F]flutemetamol PET. Emerging amyloid pathology was defined in two different ways for checking results consistency: (1) Participants with less than 40 CL and a positive Aß42/40 ratio to be compared with those having less than 20 CL and a negative ratio (amyloid‐negative) and those with more than 40 CL and a positive ratio (amyloid‐positive). (2) Participants having between 20‐40 CL to be compared with those having less than 20 CL (amyloid‐negative) and more than 40 (amyloid‐positive). All CSF biomarker levels were compared between the emerging amyloid and its corresponding amyloid‐negative and ‐positive groups. SPM12 was used to seek for differences in gray matter volumes (GMv) among groups, after accounting for age, sex, APOE, education.Result89 and 16 participants fulfilled emergent amyloid criteria 1 and 2 respectively (demographics Table 1). Compared to the amyloid‐negative group, significantly increased levels of CSF p‐tau, t‐tau, neurogranin, and NfL could already be observed in the emerging amyloid group (both definitions, Figure 1a), whereas the remaining biomarkers only demonstrated increased abnormality in the amyloid‐positive group. Subjects with emerging amyloid pathology compared with the amyloid‐negative ones had greater GMv in the angular, supramarginal, fusiform, anterior temporal and medial frontal pole (Figure 1b). The association of the GMv differences and its interactions with the different biomarkers will also be presented.ConclusionThese results provide evidence that multiple biological pathways, such as tau, synaptic and neurodegenerative, are already altered in participants with emergent amyloid pathology, which also have greater gray matter volumes. Therefore, intervening very early in the Alzheimer’s continuum may be a priority.