Diet enriched in omega-3 fatty acids alleviates olfactory system deficits in APOE4 transgenic mice

Eur J Neurosci. 2021 Nov;54(9):7092-7108. doi: 10.1111/ejn.15472. Epub 2021 Oct 13.


Olfactory dysfunction is observed in several neurological disorders including Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). These deficits occur early and correlate with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite extensive human studies, there has been little characterization of the olfactory system in models of AD. In order to determine if olfactory structural and/or molecular phenotypes are observed in a model expressing a genetic risk factor for AD, we assessed the olfactory bulb (OB) in APOE4 transgenic mice. A significant decrease in OB weight was observed at 12 months of age in APOE4 mice concurrent with inflammation and decreased NeuN expression. In order to determine if a diet rich in omega-3s may alleviate the olfactory system phenotypes observed, we assessed WT and APOE4 mice on a docosahexaenoic acid (DHA) diet. APOE4 mice on a DHA diet did not present with atrophy of the OB, and the alterations in NeuN and IBA-1 expression were alleviated. Furthermore, alterations in caspase mRNA and protein expression in the APOE4 OB were not observed with a DHA diet. Similar to the human AD condition, OB atrophy is an early phenotype in the APOE4 mice and concurrent with inflammation. These data support a link between the structural olfactory brain region atrophy and the olfactory dysfunction observed in AD and suggest that inflammation and cell death pathways may contribute to the olfactory deficits observed. Furthermore, the results suggest that diets enriched in DHA may provide benefit to APOE4 allele carriers.

Keywords: APOE4; Alzheimer disease; apoptosis; caspases; docosahexaenoic acid; mild cognitive impairment; mouse model; olfactory system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / complications
  • Alzheimer Disease* / genetics
  • Animals
  • Apolipoprotein E4* / genetics
  • Atrophy
  • Diet
  • Disease Models, Animal
  • Docosahexaenoic Acids / physiology*
  • Mice
  • Mice, Transgenic
  • Olfaction Disorders / diet therapy*
  • Olfaction Disorders / etiology
  • Olfaction Disorders / genetics
  • Olfactory Bulb* / growth & development
  • Olfactory Bulb* / metabolism
  • Olfactory Bulb* / pathology


  • Apolipoprotein E4
  • Docosahexaenoic Acids