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bioRxiv · 10.1101/2023.12.13.571584

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

Onos, K. D.·Lin, P. B.·Pandy, R. S.·Persohn, S. A.·Burton, C. P.·Miner, E. W.·Eldridge, K.·Foley, K. E.·Howell, G. R.·Territo, P. R.
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Abstract

STRUCTURED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSAlzheimers disease (AD) is the most common cause of dementia worldwide, with apolipoprotein {varepsilon}4 (APOE{varepsilon}4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODSPET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTSAll 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{varepsilon}4/{varepsilon}4 exhibited significant Type-1 uncoupling ({downarrow} glucose uptake, {uparrow} perfusion) at 8 and 12 mo, while APOE{varepsilon}3/{varepsilon}4 demonstrated Type-2 uncoupling ({uparrow} glucose uptake, {downarrow} perfusion), while immunopathology confirmed cell specific contributions. DISCUSSIONThis work highlights APOE{varepsilon}4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.

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Onos, K. D., Lin, P. B., Pandy, R. S., Persohn, S. A., Burton, C. P., Miner, E. W., Eldridge, K., Foley, K. E., Howell, G. R., Territo, P. R.. 2023-12-14. Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction. https://doi.org/10.1101/2023.12.13.571584

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