Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer’s disease

Jordan N. Williamson, Shirley A. James, Sean P. Mullen, Bradley P. Sutton, Tracey Wszalek, Beni Mulyana, Peter Mukli, Andriy Yabluchanskiy, Alzheimer’s Disease Neuroimaging Initiative Consortium, Yuan Yang

Research output: Contribution to journalArticlepeer-review


As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer’s disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer’s disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer’s participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

Original languageEnglish (US)
StateE-pub ahead of print - Apr 10 2024


  • Alzheimer’s disease (AD)
  • Apolipoprotein E
  • Functional connectivity
  • Sex difference

ASJC Scopus subject areas

  • Aging
  • veterinary (miscalleneous)
  • Complementary and alternative medicine
  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine


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