Association of β‐amyloid, microglial activation, hypermetabolism and hypertrophy in Alzheimer’s disease

Abstract

AbstractBackgroundPlasma β‐amyloid (Aβ) Aβ42/Aβ40 measured by immunoprecipitation and liquid chromatography‐mass spectrometry assay has been demonstrated useful to identify Aβ PET positive individuals, but the concordance and discordance about the positivity of plasma Aβ42/Aβ40 (Plasma+/‐) and Aβ PET (PET+/‐) have not been fully characterized. Moreover, the association of Aβ deposition, cortical thickness (CTh), glucose metabolism, and microglial activation among different Plasma/PET profiles is poorly understood.MethodIn this study, we classified 173 ADNI participants into Plasma‐/PET‐ (N = 48), Plasma+/PET‐ (N = 43), and Plasma+/PET+ (N = 73) group based on thresholds of composite Aβ PET (18F‐florbetapir, FBP) standardized uptake value ratio (SUVR) (≥1.11) and plasma Aβ42/Aβ40 (≤0.1218). Part of them had longitudinal 18F‐fluorodeoxyglucose (FDG) PET, structural MRI, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) data. Baseline and slopes of FBP SUVRs of 68 Freesurfer‐defined ROIs were compared between different Plasma/PET groups. The associations of regional FBP SUVRs, CSF sTREM2, regional glucose metabolism (reflected in FDG‐SUVR), and CTh (measured using structural MRI) were investigated in different Plasma/PET groups.ResultPlasma Aβ42/Aβ40 might become positive earlier than Aβ PET (Fig.1A, McNemar’s test, p<0.001). Longitudinally, Plasma+/PET‐ participants showed faster rates of Aβ accumulation in bilateral BANKSSTS, supramarginal, and superior parietal cortices whereas demonstrated no difference in baseline FBP SUVRs than Plasma‐/PET‐ participants (Fig.1D‐E). Higher CSF sTREM2 level and faster rate of CSF sTREM2 increase were related to slower rates of Aβ accumulation in BANKSSTS (standardized β (βstd) = ‐0.418, p = 0.002) in Plasma+/PET+ but not in Plasma+/PET‐ individuals (Fig.2A and D). In contrast, thicker CTh (Fig. 4B‐C) and higher glucose metabolism (Fig. 4H‐I) in supramarginal and superior parietal cortices were coupled to faster rates of CSF sTREM2 increase in Plasma+/PET‐ rather than in Plasma+/PET+ individuals.ConclusionThese findings suggest that plasma Aβ42/Aβ40 might become abnormal earlier than Aβ PET, and plasma Aβ42/Aβ40 positive Aβ PET negative (Plasma+/PET‐) individuals accumulate Aβ plaques faster than Plasma‐/PET‐ individuals. Activated microglia may play a role in reducing fibrillar‐Aβ increasing rates in late amyloidosis stage, whereas it may be related to hypertrophy and hypermetabolism in early amyloidosis stages.