How APOE Risk Variants Affect Brain Metabolism in the Lead-up to Alzheimer’s

Researchers uncover a potential association between an APOE genetic variant and changes in brain metabolism leading to increased risk of Alzheimer’s disease and cognitive impairment.

What: Researchers find that people who carry ɛ3/ɛ4 variations of the APOE gene have increased plasma glucose levels and decreased apolipoprotein E levels, which they characterize as a “hazardous combination” likely to accelerate neurodegeneration and increase the risk for Alzheimer’s disease (AD), in part by altering brain function and changing its ability to generate energy.

Where: Edlund A, et al. Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ɛ3/ɛ4 Carriers, Journal of Alzheimer’s Disease, 2021.

BrightFocus Connection: This project was supported by an Alzheimer’s Disease Research (ADR) grant to senior author Henrietta Nielsen, PhD, assistant professor and principal investigator in neurochemistry at Stockholm University in Sweden.

Why it is Important: The brain has outsized energy needs compared to the rest of the body, and glucose is the fuel the brain needs to run smoothly. When the process to make this fuel (glucose metabolism) is altered, it can negatively affect cognitive function. The APOE gene produces the apoE protein which is involved in the transport of fats and cholesterol through the blood. There are three common APOE alleles, e2, e3, and e4, with the e4 allele increasing risk of AD. One allele is inherited from each parent, resulting in different combinations or genotypes. APOE e4 carriers show significant changes in brain glucose metabolism years before symptoms of AD.  Previous work from Dr. Nielsen showed that cognitively healthy people harboring the APOE e3/e4 gene variant have decreased glucose metabolism in the hippocampus – an important brain region involved in learning and memory.

The idea that plasma apoE may affect glucose metabolism in the brain is controversial since plasma apoE cannot cross the blood-brain barrier. Therefore, Dr. Nielsen and her team investigated the potential causes for altered brain metabolism in people with APOE e3/e4 gene variants. About 15-20 percent of the general population shares this genetic make-up. It was hypothesized that plasma apoE levels may be related to plasma glucose and insulin levels which, can affect glucose metabolism in the brain. This is supported by findings that high plasma glucose is associated with type 2 diabetes, which also increases AD risk.

Cognitively healthy individuals who had the APOE e3/e4 genotype were recruited to undergo neuropsychological testing to measure cognitive function and to also provide blood samples for plasma analysis of apoE3 and apoE4 levels. In addition, about 25 participants underwent brain imaging with FDG-PET, to measure glucose metabolism, and structural MRI to detect any brain abnormalities. The team found that having low plasma apoE3 levels was associated with higher plasma glucose levels. This effect was most noticeable among males and overweight individuals (ie, people with a body mass index (BMI) over 25). Other studies have similarly linked high plasma glucose levels to increased body fat and male sex, rather than age, which may reflect abnormal glucose production in the liver. While this study shows a relationship between apoE levels and peripheral glucose expression, it is unclear whether apoE and glucose can directly modulate each other.

Higher plasma glucose level was not directly correlated with cognitive impairment. However, people with higher plasma glucose levels were more likely to do worse on memory and visuospatial tests. Dr. Nielsen and her team speculate that having low plasma apoE levels and high plasma glucose can lay the groundwork for accelerating neurodegeneration, leading to mild cognitive impairment, and eventually AD dementia.

Pinpointing the differences in brain metabolism in APOE ɛ3/ɛ4 carriers and other AD risk genotypes may provide important new clues about how Alzheimer’s starts and develops over decades, and where it may be possible to intervene early and potentially prevent the disease in susceptible individuals based on their genetic makeup (aka, a “personalized medicine” approach to treating the disease).