Glial activation may mediate Alzheimer’s disease progression

Abstract

AbstractBackgroundGlial activation may precede regional tau progression through Braak stages in Alzheimer’s Disease (AD)[1]. However, the role of glial activity in the temporal progression of AD is not well characterized.MethodNineteen controls and 22 patients with clinical diagnosis of MCI or AD underwent [18F]florbetaben, [18F]MK‐6240, and [11C]PBR28 PET to measure β‐amyloid, tau, and TSPO (a glial biomarker). Standard uptake value ratios and corrected gray matter volume (%GM) were calculated from prefrontal, temporal, and parietal regions to create composite AD‐centric measures for β‐amyloid, TSPO, and neurodegeneration. Braak‐specific gray matter volumes were used to measure tau and neurodegeneration in early (I/II), middle (III/IV) and late (V/VI) Braak regions. Tau and TSPO were measured with (‐PVC) and without partial volume correction. Correlation analyses were performed between TSPO and β‐amyloid, tau, and MMSE scores. Mediation analyses explored the effect of TSPO in the steps along a proposed model for AD progression (Fig 1).ResultGreater TSPO‐PVC was associated with greater β‐amyloid (std.β=0.38, p=0.015), and with greater tau‐PVC in middle (std.β=0.45, p=0.004) and late Braak regions (std.β=0.50, p=0.002, Fig 2), even after controlling for %GM. Greater TSPO‐PVC was associated with lower MMSE score (std.β=‐0.53, p=0.006). Similar results were observed for uncorrected PET data. TSPO‐PVC mediated the relationship between tau‐PVC in early Braak regions and tau‐PVC in middle Braak regions (indirect effect=0.118, p=0.017) and the relationship between tau‐PVC in middle Braak regions and neurodegeneration in middle Braak regions (indirect effect=‐0.255, p=0.027). TSPO‐PVC mediated the relationship between neurodegeneration and impaired MMSE performance for early (indirect effect=0.233, p=0.021) and middle Braak regions (indirect effect=0.204, p=0.029), and between neurodegeneration and impaired Trails B performance for early (indirect effect=0.283, p=0.009) and middle Braak regions (indirect effect=0.228, p=0.017).ConclusionTSPO is related to β‐amyloid burden, tau pathology in middle and late Braak regions, and cognitive impairment in a manner independent of neurodegeneration. Our results suggest that glial activity impacts the progression of tau pathology from early to middle Braak regions and influences the relationship between neurodegeneration and cognitive impairment in these same regions.Reference: 1. Pascoal, T.A., et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med 27, 1592–1599(2021).