Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Charles E. Seaks, Erica M. Weekman, Tiffany L. Sudduth, Kevin Xie, Brandi Wasek, David W. Fardo, Lance A. Johnson, Teodoro Bottiglieri, Donna M. Wilcock

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

Original languageEnglish
Pages (from-to)771-787
Number of pages17
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number5
StatePublished - May 2022

Bibliographical note

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this study was provided by the National Institute of Neurological Disorders and Stroke [RO1 NS097722 (DMW), 5T32NS077889-09 (CES)], National Institute on Aging [RF1 AG057754 (DMW), R56 AG057191-02 (DWF & KX), R01 AG060056 (LAJ) & R01 AG062550(LAJ)], & National Institute of General Medical Sciences [5T32GM118292-02 (CES). Acknowledgements

Publisher Copyright:
© The Author(s) 2022.


  • APOE
  • VCID
  • inflammation
  • metabolism

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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