BACKGROUND: Alzheimer9s disease (AD) is the most common cause of dementia worldwide, with apolipoprotein e4 (APOEe4) being the strongest genetic risk factor.  Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging of 18F-FDG and 64Cu-PTSM was used to assess metabolism-perfusion profiles in both sexes of aging C57BL/6J, and APOEe3/e3, APOEe4/e4, and APOEe3/e4. RESULTS: Across all strains, 8 months is a key transition stage. Females exhibited the greatest number of regional changes for both tracers, which correlate with GO-term enrichments for glucose metabolism, perfusion and immunity. Our neurovascular uncoupling analysis revealed APOEe4/e4 exhibited significant Type-1 uncoupling at 8 and 12 months, while APOEe3/e4 demonstrated significant Type-2 uncoupling by 8 months. DISCUSSION: This work highlights APOEe4 status determines key differences in progression to neurovascular uncoupling. Our method detects changes in neurovascular coupling, and may serve as an early diagnostic biomarker.

Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction