A Genetic Link Between Two Illnesses

Authored by: Kanae Funabiki

Art by: Caitlin Sweeney

“Would you rather have Alzheimer’s or skin cancer?” This sounds like an impossible theoretical question, like choosing between the ability to fly or to turn invisible. In reality, you don’t get a choice, and you probably wouldn’t want one either. But what if I told you that Alzheimer’s and cancer are both influenced and shaped by the exact same gene? Meet the gene Apolipoprotein E (ApoE), a lipoprotein responsible for regulating cholesterol levels and helping cellular repair within our bodies (1). Along with having several different functions, studies reveal that ApoE substantially affects the risk for both Alzheimer’s disease and the spread of melanoma, a type of skin cancer. The risks are highly dependent on the type of the ApoE gene an individual carries. 

Humans carry one of three variants of the ApoE gene [2]: 

● ApoE3: Found in ~75% of people 

● ApoE2: ~10% 

● ApoE4: ~14% 

The three variants have nearly the same DNA, but they differ by just one or two amino acids, also known as the building blocks of proteins [1]. Each variant binds to certain lipids or receptors in slightly different manners, changing its effects on the body [3]. From these small differences in their DNA, each ApoE allele type exhibits different effects towards the development of Alzheimer’s disease. In particular, ApoE4 triples the risk of developing the neurodegenerative disorder, while ApoE3 andApoE2 protect against the disease [4]. 

Interestingly, ApoE also plays a significant role in limiting the spread of melanoma skin cancer [5]. Researchers have found that ApoE can suppress tumor growth, prevent angiogenesis (blood vessel formation), and even help the immune system recognize and attack cancer cells [5]. Similar to Alzheimer's disease, the three alleles of ApoE hold varying capabilities for preventing the spread of melanoma. Fascinatingly, ApoE4, the variant that increases the risk of Alzheimer’s disease, is actually the most effective at suppressing the spread of melanoma [6]. In contrast,

ApoE2, which protects the brain against Alzheimer’s, is the least effective at stopping cancer progression. 

Despite decades of research, there is limited understanding of why ApoE affects Alzheimer's and melanoma in such different ways. Researchers are just beginning to explore gene editing to transform ApoE4 into ApoE2 in hopes of protecting against Alzheimer’s disease [7]. However, it is important to consider that successfully performing this gene edit could lead to increasing cancer risk in patients since ApoE2 increases the risk of melanoma while protecting the brain. This makes future efforts to alter a person’s genotype complicated, possibly trading one devastating disease for another. Going forward, it will be challenging to design therapies that only mimic the protective effects of an ApoE variant. 

So, which ApoE variant would you like to have? Dr. Grecius, a neurologist at Stanford University School of Medicine, surprisingly recommends not to test if you don’t have symptoms of disease, stating that “it will only cause grief at this point” [7]. Since we do not hold the power to change our genes, we must embrace uncertainty while forging forward with new, innovative research. 

References 

1. Ostendorf, B. N., Patel, M. A., Bilanovic, J., Hoffmann, H. H., Carrasco, S. E., Rice, C. M., & Tavazoie, S. F. (2022). Common human genetic variants of APOE impact murine COVID-19 mortality. Nature, 611(7935), 346–351. 

2. Trafton, A. (2018). Neuroscientists discover roles of gene linked to Alzheimer’s. MIT News. https://news.mit.edu/2018/neuroscientists-discover-roles-gene-linked-alzheimers-0531 

3. Husain, M., Lauren, B., & Plourde M. (2021). APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics. Front. Neurosci., 17, Sec. Neurodegeneration

4. Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021). APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. The Lancet. Neurology, 20(1), 68–80. 

5. Pencheva, N., Tran, H., Buss, C., Huh, D., Drobnjak, M., Busam, K., & Tavazoie, S. F. (2012). Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis. Cell, 151(5), 1068–1082. 

6. Ostendorf, B. N., Bilanovic, J., Adaku, N., Tafreshian, K. N., Tavora, B., Vaughan, R. D., & Tavazoie, S. F. (2020). Common germline variants of the human APOE gene modulate melanoma progression and survival. Nature medicine, 26(7), 1048–1053. https://doi.org/10.1038/s41591-020-0879-3 

7. Belluck, P. (2024). Study Suggests Genetics as a Cause, Not Just a Risk, for Some Alzheimer’s. The New York Times. 

https://www.nytimes.com/2024/05/06/health/alzheimers-cause-gene-apoe4.html