Onos, KristenLin, Peter B.Pandey, Ravi S.Persohn, Scott A.Burton, Charles P.Miner, Ethan W.Eldridge, KierraNyandu Kanyinda, JonathanFoley, Kate E.Carter, Gregory W.Howell, Gareth R.Territo, Paul R.2024-05-222024-05-222024-03-13Onos K, Lin PB, Pandey RS, et al. Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction. Preprint. bioRxiv. 2024;2023.12.13.571584. Published 2024 Mar 13. doi:10.1101/2023.12.13.571584https://hdl.handle.net/1805/40917Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 (APOEε4) 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 APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 mo, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. Discussion: This work highlights APOEε4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalAPOEAlzheimer’s diseaseMetabolismPerfusionUncouplingArticle