Neuroinflammation demonstrated by (11)C-ER176 PET with amyloid and tau pathology.

INTRODUCTION: Understanding neuroinflammation across the Alzheimer's disease (AD) spectrum is essential to elucidate disease mechanisms and individualize therapy. METHODS: Human microglial translocator protein (TSPO) expression under inflammatory stimuli was assessed by immunoblot experiments. Ninety-six participants were enrolled across four groups: cognitively unimpaired amyloid (CU A) + and -, mild cognitive impaired (MCI) A+, and Alzheimer's disease dementia (ADD) A+. Neuroinflammation using (11)C-ER176 TSPO positron emission tomography (PET) was compared to amyloid and tau PET. Correlations between neuroinflammation, amyloid, and tau pathology were examined across disease stages. RESULTS: TSPO was upregulated in human microglia under AD-like inflammatory conditions. Neuroinflammation, defined by PET TSPO, increased in CU A+ participants and became more widespread with increasing disease severity, aligning with worsening amyloid and tau pathology. Associations with tau were particularly extensive in temporal and parietal regions. DISCUSSION: These findings suggest probable amyloid association with early microglial activation, while tau pathology is closely tied to wider distribution of neuroinflammation. HIGHLIGHTS: TSPO expression increases in human microglia under AD-like inflammation. (11)C-ER176 PET shows stage-dependent neuroinflammation across the AD spectrum. Neuroinflammation overlaps with tau and is more widespread in amyloid-positive individuals. Activity peaks in MCI, stabilizes later, and relates to vascular and neurodegenerative changes.