Should you get genetic testing for your APOE isoform?

Genetic testing is an increasingly important medical tool for diagnosing patients, and recently at-home kits are now offered commercially for everything from our ancestry, to the ancestry of our pets, to our traits like facial features and sense of taste. After providing a saliva sample, these kits extract your DNA, the blueprint for all your genetic information, then look for small changes in the sequence. An ancestry kit will look for specific small differences in the sequence, called ‘single nucleotide polymorphisms’, that are common to groups of people or regions. Whereas kits for traits examine specific locations in the DNA sequence to determine which version you have of a gene, the small portion of the DNA sequence containing the instructions for a particular attribute. Predisposition kits, similarly to trait kits, look at specific genes, but focus on genes that are associated with a particular disease.

As a scientist, I may be more curious than the average person to know my genetic results, but I understand the potential double-edged sword that comes with this knowledge. Would I be prepared to know that I am at higher risk for a disease, such as breast cancer, Type 2 Diabetes or Alzheimer’s disease (AD)? For some, the answer to this question is yes, because it means having the knowledge to take action, potentially make lifestyle changes that could prevent the disease from occurring. For example, eating healthier and exercising to offset an increased genetic risk for Type 2 Diabetes. It is worth thinking through the potential impact to your mental health, your lifestyle and maybe even your health insurance policy before taking a genetic test.

Recently, Chris Hemsworth had genetic testing performed as part of the docuseries Limitless, which examined potential methods to delay aging. He found out that he carried 2 copies, or alleles, for the version of the apolipoprotein E (APOE) gene that puts him at a higher risk of developing Alzheimer’s disease (AD). AD is a progressive disease characterized by memory loss, but underlying the loss of neurological function are the accumulation of amyloid-β (Aβ) plaque deposition, hyperphosphorylated tau aggregates called neurofibrillary tangles, excessive inflammation from overactive immune responses and neuronal death.

For each gene, an individual carries 2 alleles that are passed from parents to offspring and can be the same, or not. Genes encode proteins, which are like small machines that have diverse functions in our cells, including but not limited to transporting, cleaving, or serving as a structural component. There are 3 APOE protein versions, or isoforms, determined by inheritance of the ε2, ε3, or ε4 allele. APOEε4 is the strongest genetic risk factor for AD, and that risk increases if 2 APOEε4 alleles are inherited [1]. Comparatively, APOE3 is the most common and has no effect on risk for AD, and APOE2 is generally considered protective against AD (Figure 1) [2]. APOE is important for neuronal maintenance and repair through its role in transporting and redistributing cholesterol and lipids, but also affects the important disease causing pathways in AD: Aβ accumulation, tau aggregation and neuroinflammation [3]. The structure, level of expression and function are all altered by the isoform, contributing to isoform-dependent differences in AD development. For example, APOE4 is less efficient in promoting Aβ degradation and clearance resulting in increased Aβ plaque deposition, while increasing pro-inflammatory responses [1,3]. 

Inheritance of a risk gene, like APOE, is not the same as inheriting the deterministic genes, like certain mutations in amyloid precursor protein, presenilin 1 or 2 [4]. Deterministic genes directly cause a disease, so the disease will develop without question. In the case of Alzheimer’s, deterministic genes cause early onset familial AD, which is rare. With risk genes, there is no certainty that the disease will develop, that is, some APOEε4 carriers never get AD whereas  APOEε4 noncarriers, APOEε3 and APOEε2 individuals, do develop AD.

Current guidelines issued by the American College of Medical Genetics and the National Society of Genetic Counselors recommend against APOE testing [5,6]. One study found that when their APOE results were disclosed, carriers tended to adopt new healthier behaviors, but they had concerns about stigmas and discrimination [7]. The study cautioned that APOE results could influence emotions, particularly at the time of learning results, self-perception and attitudes about memory. The Alzheimer’s Association also cautions against routine genetic screening for risk of Alzheimer’s in healthy individuals, but especially without meeting with a genetic counselor [8]. Lack of medical intervention was another reason for the recommendation against APOE testing, so these recommendations could change as therapeutics become available , which looks promising based on the ongoing clinical trial results. If you are truly interested in genetic testing, your best option is to speak to your medical doctor or seek out a genetic counselor to help make an informed decision, best understand results and ways forward.

References:

1. Yamazaki, Y. et al. (2019) Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nature Reviews Neurology 15, 501-518. 10.1038/s41582-019-0228-7

2. Wu, L. and Zhao, L. (2016) ApoE2 and Alzheimer's disease: time to take a closer look. Neural Regen Res 11, 412-413. 10.4103/1673-5374.179044

3. Husain, M.A. et al. (2021) APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics. Frontiers in Neuroscience 15. 10.3389/fnins.2021.630502

4. Blacker, D. and Tanzi, R.E. (1998) The Genetics of Alzheimer Disease: Current Status and Future Prospects. Archives of Neurology 55, 294-296. 10.1001/archneur.55.3.294

5. Goldman, J.S. et al. (2011) Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med 13, 597-605. 10.1097/GIM.0b013e31821d69b8

6. Goldman, J.G. et al. (2018) Cognitive impairment in Parkinson's disease: a report from a multidisciplinary symposium on unmet needs and future directions to maintain cognitive health. NPJ Parkinsons Dis 4, 19. 10.1038/s41531-018-0055-3

7. Largent, E.A. et al. (2021) Disclosing Genetic Risk of Alzheimer's Disease to Cognitively Unimpaired Older Adults: Findings from the Study of Knowledge and Reactions to APOE Testing (SOKRATES II). J Alzheimers Dis 84, 1015-1028. 10.3233/jad-210675

8. (2022). Genetic Testing.  Alzheimer’s Association

Edited by Alexandra Fink