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The APOE Gene, a Precursor to Alzheimer’s Disease

Written by Jinho Kim ‘26

Edited by Josephine Chen ‘24

Many people wonder if Alzheimer’s Disease runs in the family. To answer that question, several factors must be considered, one of those being genetics. Genes are molecular instructions that code for the body’s functioning cells, and they are passed down from an individual’s biological parents. Each person inherits a unique set of genes, creating slight differences in the balance and prevalence of complex traits of the body. These genetic variants may change a person’s susceptibility to a particular disease. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor [1].


Recently, the apolipoprotein E (APOE) gene has been in the spotlight of many scientific journals as a genetic risk factor for Alzheimer’s disease [2]. This protein attracts fat and forms clumps called lipoproteins. An important function of lipoproteins is packaging cholesterol and transporting it through the body, whether it be for metabolic use or disposal as waste. When the APOE gene appropriately codes for lipoproteins, they perform an essential role of maintaining normal cholesterol levels in the body [3]. Variations in the genetic code, or alleles, for APOE, can lead to variable function and effectiveness of lipoproteins.


There are at least three major alleles of the APOE gene. APOE ε3 is the most common allele and is believed to play a neutral role in the disease. The APOE ε2 allele is a rarer form of the gene and may actually provide protection against Alzheimer’s disease. Finally, the APOE ε4 allele increases risk and decreases the age of onset for Alzheimer's disease. About 25 percent of people carry one copy of APOE ɛ4, and 2 to 3 percent carry two copies, which results in an even greater risk of developing Alzheimer’s disease [1].


It is important to note, however, that the APOE gene does not definitively result in Alzheimer’s disease. Although individuals who carry the more Alzheimer’s resistant APOE ε2 allele have developed the disease, those carrying the more Alzheimer’s susceptible APOE ε4 allele may never develop symptoms. Databases have shown that about 25 percent of people with one APOE4 gene develop the disease by the age of 85, yet there are still many factors that can delay the onset of the disease [4]. On the other hand, there are also non-genetic factors that increase susceptibility to Alzheimer’s disease, such as high blood pressure, heart disease, and diabetes [3].


More research on how exactly the APOE ε4 gene can lead to Alzheimer’s disease has recently been done by neuroscientist Dr. Li-Huei Tsai at the Massachusetts Institute of Technology. Her research explores how defective apolipoprotein E triggers oligodendrocytes, which are connective tissues that provide insulation in the nervous system, to accumulate excess cholesterol [5]. These defects in cholesterol processing led to the protective wrapping of neurons being damaged, resulting in ineffective insulation of neurons. Follow-up studies by Tsai using microglia, another type of insulation cell in the nervous system, have bolstered this conclusion, claiming that abnormal disturbances observed in Alzheimer’s disease patients harboring APOE ε4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells [6]. This damage to insulating cells accumulates over time, which removes myelin from neurons. The loss of insulating properties from myelin results in slower electrical signaling of neurons and thus a decline in cognitive function.


When researchers followed up their study by treating APOE ε4-carrying mice with cyclodextrin, a drug which stimulates cholesterol removal, they observed an overall decrease of cholesterol in the brain and a boost to the animals’ cognitive performance [5]. In addition, a treatment program managed by the manufacturer of cyclodextrin has documented improvements in a human Alzheimer’s patient taking the drug [7]. One important thing to note, however, is that the brain does need set levels of cholesterol to function effectively. It is the maldistribution, not the presence of cholesterol, that causes the protective wrapping of neurons to be damaged. Thus, cyclodextrin is an ineffective solution, as it acts to deplete cholesterol equally from all parts of the brain. Other studies have shown promising results, such as the supplementation of choline, a soluble phospholipid precursor, to effectively restore the cellular lipid levels to its basal state in cells expressing APOE ε4 [8]. With further research on cyclodextrin and choline, a cure for Alzheimer’s may lie within controlling cholesterol distribution in the brain.


Because apolipoprotein E is expressed through the APOE gene, brain areas with high APOE prevalence and activity sustain the most damage [9]. Dr. Brian A. Gordon, an assistant professor of radiology at the Washington University School of Medicine in St. Louis, notes that there are some rare, atypical forms of Alzheimer’s in which people first develop language or vision problems rather than memory problems. This abnormal expression can be attributed to APOE activity in specific areas of the brain [10]. These atypical cases thus indicate that there are still many uncertainties regarding the various biological mechanisms that lead to the development of Alzheimer’s disease.


Genetics play a huge role in our development and health as we age. However, that is not to say that we are subjected to a predetermined fate. Epigenetics has constantly highlighted the role our conscious decisions and environment play in determining our health. Maintaining an active lifestyle and getting good sleep are some of the best ways to reduce one’s risk of developing Alzheimer’s disease [11]. Small, positive lifestyle changes are currently the best preventative method for Alzheimer’s. Genetics are not determinate.

 

References

1. Alzheimer’s Disease Genetics Fact Sheet [Internet]. National Institute on Aging. 2019 [cited 2022 Dec 4]. Available from: https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet

2. Dolgin E. This is how an Alzheimer’s gene ravages the brain. Nature. 2022 Nov 16;611(7937):649–649.

3. APOE gene: MedlinePlus Genetics [Internet]. MedlinePlus. 2021 [cited 2022 Dec 4]. Available from: https://medlineplus.gov/genetics/gene/apoe/

4. Oleksiw B. What are the early signs of Alzheimer’s and am I at risk? [Internet]. The Jackson Laboratory. 2019 [cited 2022 Dec 4]. Available from: https://www.jax.org/news-and-insights/2019/December/will-i-get-alzheimers

5. Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature. 2022 Nov;611(7937):769–79.

6. Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8.

7. Thomas J. Cyclo Therapeutics Announces New Positive Safety and Efficacy Data from Ongoing Phase 1 Open-Label Extension Study of Trappsol® Cyclo™ for the Treatment of Niemann-Pick Disease Type C1 [Internet]. cyclotherapeutics. 2021 [cited 2022 Dec 4]. Available from: https://cyclotherapeutics.com/cyclo-therapeutics-announces-new-positive-safety-and-efficacy-data-from-ongoing-phase-1-open-label-extension-study-of-trappsol-cyclo-for-the-treatment-of-niemann-pick-disease-type-c1/

8. Sienski G, Narayan P, Bonner JM, Kory N, Boland S, Arczewska AA, et al. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Science Translational Medicine. 2021 Mar 3;13(583):eaaz4564.

9. Dincer A, Chen CD, McKay NS, Koenig LN, McCullough A, Flores S, et al. APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression. Science Translational Medicine. 2022 Nov 16;14(671):eabl7646.

10. Bhandari T. Study yields clues to why Alzheimer’s disease damages certain parts of the brain [Internet]. Washington University School of Medicine in St. Louis. 2022 [cited 2022 Dec 4]. Available from: https://medicine.wustl.edu/news/study-yields-clues-to-why-alzheimers-disease-damages-certain-parts-of-the-brain/

11. Reducing Risk of Alzheimer’s Disease [Internet]. Centers for Disease Control and Prevention. 2022 [cited 2022 Dec 4]. Available from: https://www.cdc.gov/aging/publications/features/reducing-risk-of-alzheimers-disease/index.htm

[Image] Kjpargeter. 3D medical background with male head with brain and DNA strands Stock Illustration 334260500 [Internet]. Shutterstock. [cited 2022 Dec 4]. Available from: https://www.shutterstock.com/image-illustration/3d-medical-background-male-head-brain-334260500


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