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

BACKGROUND: Alzheimer's 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 was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEe4/e4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 mo, while APOEe3/e4 demonstrated Type-2 uncoupling (increased glucose uptake, decreased perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEe4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.