Reactive Astrogliosis predicts Amyloid Accumulation before the Preclinical Stage of Alzheimer's Disease

Abstract Background Monoamine Oxidase‐B (MAO‐B) is overexpressed in reactive astrocytes, playing a crucial role in neurodegeneration. Recently, increased binding of the PET MAO‐B tracer 18 F‐SMBT‐1 has been shown in preclinical Alzheimer's disease (AD) stages. However, the regional distribution and effect on Ab of abnormal 18 F‐SMBT‐1 binding along the AD continuum remains unclear. Method 144 Cognitively Unimpaired (CU), 24 A+ Mild Cognitive Impairment (MCI), and 20 A+ AD subjects underwent PET imaging with 18 F‐NAV4694, 18 F‐MK6240, and 18 F‐SMBT‐1. Aβ and tau PET SUVR were transformed into Centiloid (CL) and CenTauR (CTR) using CapAIBL. A+ was defined as >15CL and T+ >14 CTR in the Meta‐Temporal. SMBT‐1 scans were spatially normalised using MR‐based CapAIBL, scaled to the cerebellar cortex and several cortical regions sampled. The relationship between SMBT‐1 binding and Aβ accumulation was assessed in a subset of 81 CU A‐. Result Distinct regional 18 F‐SMBT‐1 binding was observed across brain regions (Figure 1). 18 F‐SMBT‐1 binding was higher in CU A+ compared to the CU A‐ in most regions, while binding in A+ MCI/AD either remained higher (in parietal/cingulate/occipital) or decreased (in frontal/caudate/putamen). Higher 18 F‐SMBT‐1 binding was also significant in CU A+ T‐ ( n = 43) (Figure 2). In CU A‐ participants with high 18 F‐SMBT‐1 retention, significantly higher Ab accumulation rates were observed compared to low 18 F‐SMBT1 (1.20CL/yr vs 0.01CL/yr, respectively, p = 0.001) (Figure 3). Furthermore, 92% of CU A‐ individuals with high 18 F‐SMBT‐1 were classified as Ab accumulators (58% in CU A‐/low 18 F‐SMBT‐1). Conclusion Unlike fluid neuroinflammation markers, 18 F‐SMBT‐1 facilitates quantitative assessment of regional differences in reactive astrogliosis across the AD continuum, as well as longitudinal change. Elevated 18 F‐SMBT‐1 in CU A‐ predicted Ab accumulation, highlighting the potential of 18 F‐SMBT‐1 as a prognostic marker in early‐stage AD while suggesting modulation of astrocytic function may be a target for AD prevention and treatment.