Microglial dynamics associate with the spatial pattern of tau deposition in early Alzheimer’s disease

BACKGROUND: Neuroinflammation is implicated in Alzheimer's disease (AD) pathogenesis, yet how changes in TSPO PET signal are associated with tau deposition, and how brain network architecture shapes this relationship remain poorly understood. METHODS: We conducted a prospective, multimodal neuroimaging study in 56 participants: 35 amyloid-positive individuals across the AD spectrum (ADS) and 21 amyloid-negative healthy controls (HC). Amyloid status was classified primarily by CSF Aβ42/Aβ40 and, when eligible CSF was unavailable, by baseline amyloid PET. Participants underwent TSPO PET using [18 F]GE-180 and resting-state fMRI at baseline. A longitudinal subgroup additionally underwent follow-up tau PET using [18 F]PI-2620 (n = 24) and repeat TSPO PET (n = 18) approximately 18 months later. RESULTS: Baseline TSPO did not differ significantly between groups. Baseline TSPO was associated with regional tau in both groups; the reciprocal association between tau and TSPO change was numerically weaker in AD, but this group difference was not statistically significant. Connectivity to baseline-TSPO epicenters was associated with higher tau in both groups, whereas connectivity to TSPO-change epicenters was associated with lower tau in AD but not controls (group-by-connectivity interaction p < 0.001, participant-level slope difference p = 0.012), a dissociation replicated in independent participants. CONCLUSION: These findings suggest that connectivity to established versus emerging TSPO epicenters carries distinct spatial information about tau in the AD spectrum, a pattern shaped by functional brain connectivity and absent in healthy controls. (ClinicalTrials.gov: NCT06224920).