Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease

<jats:sec><jats:title>Objective</jats:title><jats:p>Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [<jats:sup>11</jats:sup>C]PiB and [<jats:sup>18</jats:sup>F]florzolotau, respectively. Myo‐inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Myo‐inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (<jats:italic>p</jats:italic> < 0.05). Myo‐inositol levels correlated with lactate levels (<jats:italic>r</jats:italic> = 0.272, <jats:italic>p</jats:italic> = 0.047). Myo‐inositol and lactate levels were positively associated with the Clinical Dementia Rating sum‐of‐boxes scores (<jats:italic>p</jats:italic> < 0.05). Significant correlations were noted between myo‐inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (<jats:italic>p</jats:italic> < 0.05).</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>We found high myo‐inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo‐inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2024;95:104–115</jats:p></jats:sec>