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 ε4 (APOE^ε4) 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 APOE^ε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 mo, while APOE^ε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions.

Discussion: This work highlights APOE^ε4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.