Microglial activation interacts with amyloid‐β to drive longitudinal tau tangle accumulation and cognitive decline

Abstract

AbstractBackgroundActivation of microglial cells in the brain, more commonly known as neuroinflammation, has often been linked to the pathophysiology of Alzheimer’s disease (AD). However, how microglial activation is associated with longitudinal tau tangle accumulation and consequent cognitive decline is poorly understood. Here, we aimed to investigate whether baseline microglial activation impacts tau tangle deposition and cognitive decline in individuals across the AD continuum.MethodWe assessed 92 individuals from the TRIAD cohort (57 cognitively unimpaired and 35 cognitively impaired) with available baseline [11C]PBR28‐PET, a measure of microglial activation and [18F]NAV4694 Aß‐PET, and longitudinal [18F]MK6240 Tau‐PET (mean follow‐up time = 1.93 years) and Mini‐Mental State Exam (MMSE) (mean follow‐up time = 1.84 years). We performed voxel‐wise associations using linear regressions accounting for age and sex and adjusted for multiple comparisons using Random Field Theory (RFT) (p < 0.05). We used the cuneus and superior temporal cortex as a composite ROI for [11C]PBR28‐PET and Aß‐PET since these regions showed a higher association with longitudinal tau accumulation in the temporal meta‐ROI.ResultVoxel‐wise analysis showed that baseline levels of [11C]PBR28‐PET alone are not sufficient to predict longitudinal tau tangle accumulation (Fig. 1a). However, the interaction between [11C]PBR28‐PET levels and Aß burden predicted an increased accumulation of tau tangle, mainly in the cuneus, inferior frontal and lateral occipital regions (Fig. 1b).Individuals with higher baseline [11C]PBR28‐PET and Aß‐PET levels present higher rates of longitudinal tau accumulation in the temporal meta‐ROI (ß = 0.36, t = 3.46, p = 0.0009; Fig. 1c). Similarly, while [11C]PBR28‐PET levels alone did not correlate with longitudinal changes in MMSE score (ß = ‐0.17, t = ‐1.69, p = 0.10), a significant interaction between [11C]PBR28‐PET and Aß‐PET levels on MMSE annual decline was observed (ß = ‐0.24, t = ‐2.25, p = 0.028; Fig. 1d).ConclusionWe found that baseline levels of microglial activation was associated with longitudinal tau tangle accumulation and cognitive decline in individuals across the AD continuum in the presence of Aß burden. Our results indicate that microglial activation might act potentiating the deleterious effects of Aß on forthcoming tau tangle deposition.