Alzheimers-associated inflammatory alterations mediate tau-associated neurodegeneration in limbic and temporal regions across clinical variants of Alzheimers disease

ObjectivesMicroglia monitor and respond to the brains microenvironment to maintain homeostasis. However, in Alzheimers disease and related dementias (ADRD), microglia may contribute to pathology. We hypothesized that AD-related inflammatory changes, measured with TSPO PET, would be locally associated with amyloid, tau, and neurodegeneration, and influence key pathways among them. MethodsParticipants (21 controls, 25 with ADRD) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimers Disease study underwent baseline amyloid PET (Florbetaben SUVR), tau PET (MK6240 SUVR), TSPO PET (ER176 SUVR), and structural MRI (gray matter volume). Cognitive assessments and consensus diagnoses (e.g., MCI, AD, PCA, FTD, LATE) were performed at the CUIMC ADRC with biomarker information when available. We evaluated regional colocalization of biomarker elevation in ADRD compared to controls, TSPO associations with ATN biomarkers, and TSPO mediations along key ATN pathways. Sensitivity analyses were stratified by amyloid positivity. ResultsElevated TSPO was spatially colocalized with elevated tau (8 regions), amyloid (7 regions), and neurodegeneration (4 regions). Higher TSPO in limbic, temporal, and parietal regions was associated with higher tau (0.8 to 2.3, p<0.03), which remained significant after adjusting for amyloid and neurodegeneration in the inferior parietal cortex. TSPO mediated the association between tau and neurodegeneration in limbic and temporal regions (-0.27 to -0.39, p<0.02; 43% to 89% of the total effect), while tau did not mediate the association between TSPO and neurodegeneration. TSPO also mediated the association between amyloid and tau, as well as tau across progressive Braak stages, but only in amyloid-positive ADRD. ConclusionAcross ADRD diagnoses with different underlying brain microenvironments (e.g., pathology/copathology) to which microglia are sensitive, higher microglia density was associated with greater tau burden and mediated tau-associated neurodegeneration. Glia may represent a promising target for intervention strategies in ADRD-associated tau and neurodegeneration.