Inflammatory alterations mediate tau-associated neurodegeneration

Microglia monitor and respond to the brain's microenvironment to maintain homeostasis. However, in Alzheimer's disease and related dementias, chronically pro-inflammatory microglia may contribute to pathology. We hypothesized that inflammatory alterations, measured as microglia density via 18 kDa translocator PET, would be elevated with a topography similar to tau, be most strongly associated with tau compared to amyloid and neurodegeneration, and mediate pathways among amyloid, tau and neurodegeneration. Participants (21 cognitively unimpaired, 25 cognitively impaired) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer's Disease study underwent baseline amyloid PET (Florbetaben standard uptake value ratio), tau PET (MK6240 standard uptake value ratio), 18 kDa translocator PET (ER176 standard uptake value ratio) and structural MRI (grey matter volume). Biomarkers were quantified in 13 a priori regions of interest. Cognitive assessments and consensus diagnoses were performed at the Columbia Alzheimer's Disease Research Center with biomarker information when available to define cognitive impairment. We evaluated cross-sectional regional colocalization of microglia density and amyloid, tau and neurodegeneration biomarker elevations in cognitively impaired individuals compared to amyloid-negative cognitively unimpaired individuals, microglia density associations with amyloid, tau and neurodegeneration biomarkers and microglia density mediation pathways among amyloid, tau and neurodegeneration. Exploratory analyses were stratified by amyloid positivity. Across all cognitively impaired individuals with different underlying brain microenvironments to which microglia are sensitive, higher microglia density colocalized with greater tau (10 regions) more often than with amyloid (8 regions) and neurodegeneration (4 regions), was associated with greater tau (β = 0.29-0.67 in cingulate, lingual and parietal regions) and neurodegeneration (β = -3.6 to -0.14 in limbic and medial temporal regions), and mediated tau-associated neurodegeneration (β = -0.44 to -0.26 in limbic, temporal and parietal regions). In the context of amyloid-positivity, microglia may also mediate amyloid-associated tau (β = 0.24-0.25 in parietal regions) and tau spreading (β = 0.09-0.12 across progressive Braak stage regions), whereas amyloid may not be necessary for tau-associated neurodegeneration, particularly in limbic regions (β = -0.46 to -0.37 in amyloid-negative individuals with cognitive impairment alone). Glia may represent a promising target for intervening on tau-associated neurodegeneration across individuals with cognitive impairment.