Attenuated Acute Microglial Responsiveness in Participants with Alzheimer's Disease: An In Vivo LPS Challenge [11C]PBR28 TSPO-PET Pilot Study

Abstract Background: Elevated TSPO-PET binding in Alzheimer's disease (AD) is widely interpreted as increased microglial activity, yet whether these cells retain functional capacity for responses protective against amyloid and other pathologies remains unknown. We conducted a proof-of-concept study using in vivo lipopolysaccharide (LPS) challenge to assess dynamic microglial responsiveness. Methods: Eleven participants (5 amyloid-negative controls, 6 amyloid-positive clinical AD) underwent serial [ 11 C]PBR28 TSPO-PET before and 3 hours after low-dose intravenous LPS (0.4 ng/kg). The prespecified primary outcome was parietal cortex microglial activity response index (MARI = [V T,post − V T,pre ]/V T,pre ). Secondary outcomes included MARI across 10 additional brain regions (FDR-corrected) and peripheral cytokines (n = 7). Given limited sample size, we prioritized effect size estimation with bootstrap 95% confidence intervals. Results: Participants with clinical AD demonstrated markedly reduced microglial activity (parietal MARI: 0.18 ± 0.13 vs 0.36 ± 0.14; Cohen's d = 1.29, bootstrap 95% CI: 0.15–2.43). The responder rate (MARI > 0.20) was 100% in controls versus 33% in AD (Fisher's p = 0.061). The magnitude of blunted responses appeared consistent across brain regions (median effect size r = 0.53; 6/11 regions survived FDR q < 0.10). Peripheral cytokine responses paralleled central findings, with IL-6 MARI correlating with parietal brain MARI (ρ = 0.70) in the paired subset (n = 5). Conclusions: This study provides preliminary in vivo evidence that AD is characterized by attenuated rather than intensified acute neuroinflammatory responses. The convergence of central and peripheral immune blunting suggests systemic dysfunction. These hypothesis-generating findings warrant replication in larger, age-matched cohorts.