Thinking with your stomach

Dr. Jacob Raber, Eileen TorresFollowing a low-fat diet linked to improved brain function

April 24, 2017

Story and photo by David Edwards

April's featured paper is titled, "Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome," published in Scientific Reports. The project was led by Jacob Raber, Ph.D., professor of behavioral neuroscience, OHSU School of Medicine. Its authors are Lance A. Johnson, Ph.D., assistant professor at the University of Kentucky and previous postdoctoral trainee in OHSU's Department of Behavioral Neuroscience; Eileen Ruth S. Torres, graduate student in the Behavioral Neuroscience Graduate Program, OHSU School of Medicine; Soren Impey, Ph.D., assistant professor of cell, developmental and cancer biology, OHSU School of Medicine; Jan F. Stevens (Fred Stevens), professor in the Department of Pharmaceutical Sciences at Oregon State University; and Dr. Raber.

Challenges of Alzheimer's disease

Alzheimer's disease (A.D.) is the most common form of dementia, which is characterized by severe memory loss and cognitive impairment that gets worse over time. There are around 5.3 million people with A.D. living in the United States, a number that is growing steadily with our increasingly aging population. Unlike other major leading causes of death in the U.S., such as heart disease or stroke, there is no way to prevent A.D., cure it or slow its progression, so research is desperately needed to identify new therapies against the disease.

When considering the frequency of A.D. in the general population, the greatest risk factors for its development are old age, having a family history of A.D. and carrying a variant of the APOE gene. APOE codes for apolipoprotein E, a protein responsible for packaging fat molecules for transport throughout the body, including the brain. There are three variants of this gene found in the general population—E2 (7 percent frequency); E3 (79 percent), considered the "neutral" or normal version of the gene; and E4 (14 percent)—which result in three different versions of the protein. People carrying the E4 variant have a 15-fold increased risk of developing A.D. compared to people with E3.

Another risk factor for developing A.D. is having diabetes, a disease in which the body no longer responds normally to insulin (called "insulin resistance"), resulting in high blood sugar. Some studies have suggested that people with both E4 and diabetes have an even higher risk of cognitive impairment and dementia. Interestingly, E4 carriers and people with diabetes share similar characteristics that are linked to cognitive impairment. For example, one of the hallmarks of A.D. is glucose hypometabolism, where the brain stops using glucose as its primary energy source. Studies have shown that the brains of otherwise healthy E4 carriers show similar evidence of glucose hypometabolism occurring in the same brain regions as those impacted by A.D.

Although having diabetes and the E4 variant share similar characteristics in terms of increasing the risk for A.D., the biological link between them hadn't been uncovered. A group of OHSU researchers, led by Dr. Raber in the Department of Behavioral Neuroscience, sought to more thoroughly investigate this link.

Dr. JohnsonMeasuring memory

Dr. Raber and colleagues tested whether insulin-resistant E4-carrying mice showed differences in brain metabolism and cognitive function compared to their E3-carrying counterparts. To do this, they gave the mice either a high-fat diet (HFD), mimicking a standard unhealthy diet and resulting in insulin resistance and type-2 diabetes or a low-fat diet (LFD) as a control.

The mice then underwent three different tests to evaluate their cognitive function. These tests indicated that diabetes, in combination with the E4 genetic variant, increases the severity of some of the memory problems associated with AD.

To explore this further, the researchers performed an "integrated 'omics" analysis, where they measured changes in DNA regulation and metabolism to identify a biological difference between the mice. They found that three interconnected pathways were affected—purine metabolism, glutamate metabolism and the pentose phosphate pathway.

Finally, the researchers asked whether the harmful changes in memory and metabolism that they observed were reversible in the E4 mice. They exposed a separate group of E4 mice to a HFD for five months, followed by a LFD for one month. Surprisingly, after changing diets, the obese E4 mice lost weight and showed significant improvements in cognitive tests.

Importantly, the "integrated 'omics" analysis also showed a reversal of the three affected pathways, matching control E4 mice. While the full implications of how these pathways are affecting memory loss require further study, it suggests that there is a biological connection between diabetes and A.D., and that their combined effect can be overcome by improving one's diet.

"We keep looking for simple links between diet and a whole host of health outcomes," said Mary Heinricher, Ph.D., associate dean for basic research, OHSU School of Medicine. "What I thought was really intriguing about this paper was their ability to tease out an interaction between genes and diet that – indirectly – contributed to cognitive impairment."

Future directions

Overall, the results of the team's study indicate that there is a biological association between diabetes and AD. Their results from dietary intervention are encouraging because they suggest that lifestyle measures such as weight loss and dietary changes may protect E4 carriers from cognitive impairment and A.D.

"In our ongoing work, we are searching for ways to rescue, delay or prevent the onset of cognitive dysfunction in E4 individuals," wrote Dr. Lance Johnson, lead author of the study, by testing the impact of short-term diet changes to rescue the cognitive performance in E4 carriers.



Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome. Sci Rep, 2017 Mar;7:43701. Lance A Johnson, Eileen Ruth S Torres, Soren Impey, Jan F Stevens, and Jacob Raber.

More Published Papers

Pictured above. Top photo: Eileen R. S. Torres, Dr. Jacob Raber. Bottom photo: Dr. Lance Johnson. 

About the OHSU School of Medicine Paper of the Month

The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Associate Dean for Basic Research Mary Heinricher, Ph.D. Learn more