| First Author | Onos KD | Year | 2024 |
| Journal | Alzheimers Dement | Volume | 20 |
| Issue | 7 | Pages | 4951-4969 |
| PubMed ID | 38713704 | Mgi Jnum | J:351101 |
| Mgi Id | MGI:7666304 | Doi | 10.1002/alz.13842 |
| Citation | Onos KD, et al. (2024) Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction. Alzheimers Dement 20(7):4951-4969 |
| abstractText | BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eepsilon4 (APOEepsilon4) 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 APOEepsilon4/epsilon4 exhibited significant Type-1 uncoupling ( downward arrow glucose uptake, upward arrow perfusion) at 8 and 12 months, while APOEepsilon3/epsilon4 demonstrated Type-2 uncoupling ( upward arrow glucose uptake, downward arrow perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEepsilon4 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 (18)F-FDG and (64)Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEepsilon3/epsilon3, hAPOEepsilon4/epsilon4, and hAPOEepsilon3/epsilon4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEepsilon4/epsilon4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEepsilon3/epsilon4 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 APOEepsilon4/epsilon4 compared with APOEepsilon3/epsilon4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker. |
