Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation





First Advisor

Dr. Steve Estus


Elucidating the relationship of the gut microbiome in Alzheimer's Disease (AD) risk and pathogenesis is an area of intense interest. Since 60 to 80% of AD risk is related to genetics and APOE alleles represent the most impactful genetic risk factors for AD, their mechanism(s) of action are under intense scrutiny.

First, I conducted a study on APOE targeted replacement mice to investigate the impact of APOE alleles on the murine gut microbiome. The relative abundance of bacteria from the family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of the class Erysipelotrichia increased with APOE4 status, a finding that extended to humans. Since Ruminococacceae have been associated with increased SCFA production, these findings suggest that SCFA-producing bacteria are increased in the AD-protective APOE2 positive mice.

Next, I compared the effects of short-chain fatty acid (SCFA)- vs. saline-treated water on APPswe/PSEN1dE9 mice maintained under standard laboratory conditions. I found that SCFA treatment increased alpha-diversity and impacted the gut microbiome profile by increasing the relative abundance of the genera Bifidobacterium and Lactobacillus, which are known to produce SCFAs and SCFA precursors. Although gut microbiome changes in SCFA-treated mice were robust, SCFA treatment did not significantly affect behavior, cortical or hippocampal astrocyte activation, or soluble and insoluble amyloid levels.

In conclusion, there is robust evidence of an APOE allelic effect on the murine gut microbiome that implies an AD-relevant genetic impact on the gut microbiome. The gut microbiome can be modulated by SCFA supplementation, revealing a potential therapeutic for AD prevention. These pioneering studies represent the medical importance of gut health on disease prevention and treatment.

Digital Object Identifier (DOI)

Funding Information

The gut microbiome studies were funded by NIH (R56AG057589-01A1). The student was also funded by an in-house grant through Sander-Brown Center on Aging (T32 GM118292-03).