Hyperpolarized 13C MRI uncovers early and progressive metabolic dysfunction in the hAPP-J20 mouse model of Alzheimer’s disease

<title>Abstract</title> <p> Impaired brain energy metabolism is an early feature of Alzheimer's disease (AD), but the standard metabolic imaging tool, [ ¹⁸ F]FDG-PET, reports only glucose uptake and cannot resolve downstream metabolic flux nor inform on overall metabolic profile of the brain. In this study, we used [ ¹⁸ F]FDG-PET, hyperpolarized (HP) [1- ¹³ C]pyruvate ¹³ C magnetic resonance spectroscopic imaging (MRSI), and ex vivo ¹H-NMR metabolomics to characterize how amyloid-β (Aβ) associated pathology reshapes brain energy metabolism in the hAPP-J20 mouse model, from glucose uptake to metabolic fluxes and steady-state metabolite concentrations. HP ¹³ C MRSI was performed in male and female wild-type (WT) and hAPP-J20 mice at 2 and 14 months of age, with FDG-PET and metabolomics acquired at the final timepoint. HP ¹³ C MRSI revealed a progressive, region-specific increase in glycolytic flux in hAPP-J20 mice, with increased apparent HP [1- ¹³ C]Lactate/Pyruvate conversion (relative to vascular delivery) localized to the hippocampus in females and to the cortex in males; HP ¹³ C urea perfusion measures confirmed comparable substrate delivery between genotypes. In contrast, [ ¹⁸ F]FDG-PET showed no genotype difference in regional glucose uptake, although the sex- and weight-dependent scaling of FDG uptake observed in the WT controls was lost in hAPP-J20 mice. <italic>Ex vivo</italic> metabolomics uncovered sex-divergent metabolic rewiring: a succinate-centered strengthening of the TCA cycle and propanoate metabolism in females, versus altered tyrosine and ubiquinone metabolism in males. These data show that HP ¹³ C MRSI detects an Aβ-associated increase in glycolytic flux before FDG-PET registers a change, and position HP ¹³ C pyruvate MRS imaging as a sensitive, radiation-free, flux-based biomarker that complements glucose-uptake imaging in AD. </p>