Obesity and APOE4: Gene-Environment Interaction in Alzheimer’s Disease
Material below summarizes the article Obesity Accelerates Alzheimer-Related Pathology in APOE4 but Not APOE3 Mice, published on June 12, 2017, in eNeuro and authored by V. Alexandra Moser, and Christian J. Pike.
Alzheimer’s disease (AD) is a complex, multi-factorial disease for which a number of genetic, environmental, and lifestyle risk factors have been identified.
For the vast majority of those afflicted, AD does not result from any single factor, but rather the interactive effects of multiple risk factors. Despite the importance of interactions among risk factors, our understanding of how the combination of these variables affects development and progression of AD is poorly understood.
In this paper, we investigated the gene-environment interaction between two well-established AD risk factors, apolipoprotein E4 (APOE4) and obesity.
APOE4 is the most significant genetic risk factor for late-onset AD. APOE4 is not a genetic mutation, but rather a polymorphism. Specifically, the APOE gene has three normal alleles termed APOE2, APOE3, and APOE4, which code for proteins that differ at only two amino acids.
APOE3, the most common of the three with a prevalence in the United States of approximately 80 percent, has a neutral effect on AD risk. APOE2 is the least common allele, carried by only approximately five percent of the population and is associated with reduced risk of AD as well as increased longevity.
APOE4 is present in approximately 15 percent of the general population, but its prevalence increases to approximately 60 percent in AD patients. There is a gene dosage effect such that people with two copies of APOE4 have a much higher likelihood of developing AD than those with a single APOE4 allele.
Although APOE4 is a strong risk factor for AD, it’s important to note a significant proportion of APOE4 carriers never develop AD. Thus, even in APOE4 carriers, the risk for AD is mediated by interactions among several genetic and environmental factors.
Another important AD risk factor is obesity.
Increased adiposity, particularly when it accumulates in the midsection of the body during middle age, increases the likelihood of developing AD and related dementias in old age by up to three-fold. Approximately two-thirds of adults in the United States are overweight or obese, making obesity perhaps the most prevalent and preventable risk factor for AD.
Whether and how obesity may interact with APOE4 is incompletely understood.
Epidemiological studies linking APOE genotype with obesity and obesity-related outcomes have yielded mixed results. It’s known APOE4 increases the risk of cardiovascular disease, presumably due to its role in cholesterol metabolism. However, the extent to which APOE4 interacts with obesity to affect AD risk has not been rigorously investigated.
In our study, we investigated hypothesized interactions between APOE genotype and obesity using transgenic male mice.
Although mice provide a highly defined and well-controlled approach, they neither develop AD nor express human APOE genotypes. To overcome these challenges, we used a genetically engineered mouse strain designed to produce pathological lesions that model AD and express either human APOE3 or human APOE4.
To understand the effects of obesity, separate groups of APOE3 and APOE4 transgenic mice were maintained on either a normal diet or a Western diet high in saturated fat and sugars. We tracked various metabolic indices over the course of the 12-week dietary treatment, including body weight and blood glucose levels, and measured their AD-related pathology at the end of the period.
As expected, male mice maintained on a Western diet showed increases in body weight, adiposity, and pre-diabetic markers compared to the mice fed a normal diet. The metabolic effects of the Western diet were similar in APOE3 and APOE4 mice.
The most interesting finding was how the Western diet differentially affected AD-related pathology in APOE3 versus APOE4 mice.
In the APOE3 mice, the levels of β-amyloid deposits, the primary neuropathological hallmark of AD, were the same in groups maintained on normal and Western diets. However, APOE4 mice fed the Western diet showed a significant increase in β-amyloid deposits in comparison to APOE4 mice fed the normal diet. Note that because APOE4 promotes AD, APOE4 mice have greater pathology than APOE3 mice regardless of diet.
Similar results were observed when we measured levels of reactive glia, which are cellular indicators of neuroinflammation. Diet-induced obesity was associated with increased reactive glial cells in APOE4 but not APOE3 mice. Because neuroinflammation is widely implicated as a causal factor in AD, and because both APOE4 and obesity increase neuroinflammation, pro-inflammatory pathways may represent a mechanism by which these factors interact.
These results demonstrate a gene-environment interaction in which the AD-promoting effects of obesity were observed only in the presence of APOE4 genotype.
Additional research is needed to understand how these findings predict outcomes in human populations, as well as to understand the role of neuroinflammation in mediating the relationships among APOE4, obesity, and AD.
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Obesity Accelerates Alzheimer-Related Pathology in APOE4 but not APOE3 Mice. V. Alexandra Moser and Christian J. Pike. eNeuro Jun 2017. DOI: https://doi.org/10.1523/ENEURO.0077-17.2017
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