By Rebecca Fleeman
We are consistently told that throughout our lives we should “eat right and exercise”. Ask anyone why diet and physical activity are important, and they will likely respond with answers on disease prevention and longevity. The general public is largely aware that a bad diet can lead to weight gain, and that overweight and obese individuals are at greater risk for diabetes and heart disease. However, this is often the extent of people’s knowledge and ultimately where their response ends; just obesity, diabetes, heart disease. While these messages are true, that conversation is not all inclusive, and should extend further. We need more public health outreach to increase society’s understanding of how the foods we eat and the steps our watches count affect a myriad of diseases. In the Proctor Lab (the lab I currently work in at Penn State College of Medicine), one of my projects focuses on the extension of this conversation, by looking at how our diet may be affecting the brain, and how this may contribute to Alzheimer’s disease risk.
When speaking with nutrition enthusiasts like myself, you may hear us mention the “SAD diet”. SAD is an appropriately fitting acronym for the Standard American Diet, also known as a Western diet, which is characterized by highly processed foods containing high levels of saturated fat and refined sugars1. Figure 1 demonstrates the embarrassingly small number of Americans currently eating the minimum amount of fruits and vegetables, and the vast majority of Americans that are surpassing the recommended intake of added sugars, saturated fats, and sodium. How does this have anything to do with Alzheimer’s disease (AD)? AD mainly affects populations over the age of 60 and is characterized by the loss of neurons, particularly in a section of the brain called the hippocampus that is important for learning and memory. While we do not know what exactly causes AD, we know that the greatest genetic risk factor for AD is carrying the ε4 variant allele for apolipoprotein E (APOE4). The APOE protein is a lipid transporter found both in the brain and in the periphery of the body. Depending on the APOE variant allele you carry (ε2, ε3, or ε4, which differ by only two amino acids), your APOE protein prefers binding to different types of lipids and changes affinity for the receptors to which it binds and delivers lipids. Roughly 14% of the population2 has the ε4 allele, and those who are homozygous for APOE4 (that is, they have two copies in their DNA) have up to 14-fold greater risk for developing AD3. Although a great deal of research has been focused at this genetic risk factor, scientists have yet to fully elucidate why APOE4 confers such great risk for AD. While APOE4 was first identified as a risk factor for AD by a group of researchers at Duke in the early 1990s4, APOE4 was not new to the scene. In fact, APOE4 had been studied since the 1970s5 due to its risk in another disease: heart disease.
The questions still remain on how does the egg, sausage, and cheese biscuit I chowed down for breakfast affect the neurons in my brain, and how does the harvest salad with whole grains and beans I consumed at lunch have a differing affect? And finally, what does this have to do with APOE4? To start, both the number of calories we eat a day and the macronutrient profile of those calories (carbohydrates, fats, and protein) have been shown to have an effect on AD pathogenesis6,7. More specifically, decreasing saturated fats like those in the egg, sausage, cheese biscuit, and increasing polyunsaturated fats like those found in nuts, seeds, and beans on the salad over your lifetime, can decrease your risk for dementia8. Additionally, there are compounds found in plant foods that have been shown to decrease AD pathology such as resveratrol found in grapes9, sulforaphane10 found in cruciferous veggies like Brussels sprouts and kale, and beta-carotene11,12 found in sweet potatoes and carrots. These compounds are just the start! Fruits, vegetables, nuts, seeds, and legumes are packed full of brain protecting nutrients. APOE4 becomes involved in this equation when we consider that APOE4 has been shown in multiple studies to increase inflammatory processes in the brain13,14 as well as increase risk for metabolic dysregulation15. Because we know the potential for our diet to also affect inflammation and metabolism, there may be specific mechanisms by which diet exacerbates the detrimental effects of APOE4 in terms of AD pathogenesis.
Previous studies have identified a role for a diet interaction with APOE in AD, showing that both peripheral metabolic parameters and AD pathology are influenced differently by APOE4 both at baseline and after consuming a Western diet16,17. However, few studies have simultaneously evaluated cardiovascular and neurodegenerative disease across the lifespan. My project tests the hypothesis that the APOE4 allele and Western diet synergize to alter immunometabolic processes in the brain. My goal is to identify how APOE4 affects both the inflammatory and metabolic activities of the brain and understand how diet modulates the APOE4 effects. In doing so, we hope to enhance future therapeutic developments for the aging population, who often present co-morbidly with cardiovascular and neurodegenerative pathology.
Alas, it is clear that your diet can affect more than just your risk for obesity, heart disease and diabetes. In addition, what we choose to put on our plate can affect risk for Alzheimer’s disease, intestinal diseases, osteoporosis, some cancers, and more6,8,10–12,18,19. I encourage you to consider how the choices you make at the grocery store now may affect your disease risk in the future. In line with this, make sure to shop the outer rim of the grocery store. This is where the fresh produce is always located. Remember that fruits and veggies were given their vibrant colors for a reason: to attract your attention to the yummy micronutrients they offer! Aim to fill the majority of your plate with whole-foods that are plant-based and full of nutrients protecting against disease.
Looking for some good, science-based resources on improving your diet? Check out some of the links below!
1. Grotto D, Zied E. The standard American diet and its relationship to the health status of Americans. Nutr Clin Pract. 2010;25(6):603-612. doi:10.1177/0884533610386234
2. Meta-analysis of all published AD association studies (case-control only) APOE_E2/3/4. ALZGENE. http://www.alzgene.org/meta.asp?geneID=83. Published 2010. Accessed June 10, 2019.
3. Liu C-C, Zhao N, Fu Y, et al. ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron. 2017;96(5):1024-1032.e3. doi:10.1016/j.neuron.2017.11.013
4. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921-923. doi:10.1126/science.8346443
5. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. 2016. doi:10.1007/s00109-016-1427-y
6. Luchsinger JA, Tang MX, Shea S, Mayeux R. Caloric intake and the risk of Alzheimer disease. Arch Neurol. 2002;59(8):1258-1263. doi:10.1001/archneur.59.8.1258
7. Pistell PJ, Morrison CD, Gupta S, et al. Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol. 2010;219(1-2):25-32. doi:10.1016/j.jneuroim.2009.11.010
8. Morris MC, Evans DA, Bienias JL, et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol. 2003;60(2):194-200. doi:10.1001/archneur.60.2.194
9. Sawda C, Moussa C, Turner RS. Resveratrol for alzheimer’s disease. Ann N Y Acad Sci. 2017;1403(1):142-149. doi:10.1111/nyas.13431
10. Lee S, Choi B-R, Kim J, et al. Sulforaphane Upregulates the Heat Shock Protein Co-Chaperone CHIP and Clears Amyloid-β and Tau in a Mouse Model of Alzheimer’s Disease. Mol Nutr Food Res. 2018;62(12):1800240. doi:10.1002/mnfr.201800240
11. Boccardi V, Arosio B, Cari L, et al. Beta-carotene, telomerase activity and Alzheimer’s disease in old age subjects. Eur J Nutr. 2020;59(1):119-126. doi:10.1007/s00394-019-01892-y
12. de Oliveira BF, Veloso CA, Nogueira-Machado JA, et al. Ascorbic acid, alpha-tocopherol, and betacarotene reduce oxidative stress and proinflammatory cytokines in mononuclear cells of Alzheimer’s disease patients. Nutr Neurosci. 2012;15(6):244-251. doi:10.1179/1476830512Y.0000000019
13. Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. 2009;30(9):1350-1360. doi:10.1016/J.NEUROBIOLAGING.2007.11.014
14. Dhungana H, Rolova T, Savchenko E, et al. Western-Type Diet Modulates Inflammatory Responses and Impairs Functional Outcome Following Permanent Middle Cerebral Artery Occlusion in Aged Mice Expressing the Human Apolipoprotein E4 Allele. Vol 10.; 2013. doi:10.1186/1742-2094-10-102
15. Nahdia S. Jones, Rebeck WG. The Synergistic Effects of APOE Genotype and Obesity on Alzheimer’s Disease Risk. Int J Mol Sci. 2018. doi:10.3390/ijms20010063
16. Moser VA, Pike CJ. Obesity Accelerates Alzheimer-Related Pathology in APOE4 but not APOE3 Mice. eneuro. 2017;4(3):ENEURO.0077-17.2017. doi:10.1523/ENEURO.0077-17.2017
17. Christensen A, Pike CJ. APOE genotype affects metabolic and Alzheimer-related outcomes induced by Western diet in female EFAD mice. FASEB J. 2019;33(3):4054-4066. doi:10.1096/fj.201801756R
18. Duan Y, Zeng L, Zheng C, et al. Inflammatory Links Between High Fat Diets and Diseases. Front Immunol. 2018;9:2649. doi:10.3389/fimmu.2018.02649
19. Spence JD. Nutrition and risk of stroke. Nutrients. 2019;11(3). doi:10.3390/nu11030647