Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction

Kristen D Onos; Peter B Lin; Ravi S Pandey; Scott A Persohn; Charles P Burton; Ethan W Miner; Kierra Eldridge; Jonathan Nyandu Kanyinda; Kate E Foley; Gregory W Carter; Gareth R Howell; Paul R Territo

doi:10.1002/alz.13842

Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction

Alzheimers Dement. 2024 May 7. doi: 10.1002/alz.13842. Online ahead of print.

Authors

Kristen D Onos¹, Peter B Lin^{2

3}, Ravi S Pandey⁴, Scott A Persohn², Charles P Burton², Ethan W Miner², Kierra Eldridge², Jonathan Nyandu Kanyinda¹, Kate E Foley^{1

2}, Gregory W Carter^{1

4}, Gareth R Howell¹, Paul R Territo^{2

5}

Affiliations

¹ The Jackson Laboratory, Bar Harbor, Maine, USA.
² Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
³ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
⁴ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
⁵ Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

PMID: 38713704
DOI: 10.1002/alz.13842

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.

Keywords: APOE; Alzheimer's disease; metabolism; perfusion; uncoupling.

Abstract

Grants and funding