Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction
| dc.contributor.author | Onos, Kristen D. | |
| dc.contributor.author | Lin, Peter B. | |
| dc.contributor.author | Pandey, Ravi S. | |
| dc.contributor.author | Persohn, Scott A. | |
| dc.contributor.author | Burton, Charles P. | |
| dc.contributor.author | Miner, Ethan W. | |
| dc.contributor.author | Eldridge, Kierra | |
| dc.contributor.author | Nyandu Kanyind, Jonathan | |
| dc.contributor.author | Foley, Kate E. | |
| dc.contributor.author | Carter, Gregory W. | |
| dc.contributor.author | Howell, Gareth R. | |
| dc.contributor.author | Territo, Paul R. | |
| dc.contributor.department | Neurology, School of Medicine | |
| dc.date.accessioned | 2024-09-17T10:37:34Z | |
| dc.date.available | 2024-09-17T10:37:34Z | |
| dc.date.issued | 2024 | |
| dc.description.abstract | Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (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 months, 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 months, 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 manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. Highlights: We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker. | |
| dc.eprint.version | Final published version | |
| dc.identifier.citation | Onos KD, Lin PB, Pandey RS, et al. Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction. Alzheimers Dement. 2024;20(7):4951-4969. doi:10.1002/alz.13842 | |
| dc.identifier.uri | https://hdl.handle.net/1805/43346 | |
| dc.language.iso | en_US | |
| dc.publisher | Wiley | |
| dc.relation.isversionof | 10.1002/alz.13842 | |
| dc.relation.journal | Alzheimer’s & Dementia | |
| dc.rights | Attribution-NonCommercial 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | |
| dc.source | PMC | |
| dc.subject | APOE | |
| dc.subject | Alzheimer's disease | |
| dc.subject | Metabolism | |
| dc.subject | Perfusion | |
| dc.subject | Uncoupling | |
| dc.title | Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction | |
| dc.type | Article |