Alzheimer’s Risk and the APOE4 Gene
Studies have long indicated that carrying two copies of the apolipoprotein E (APOE) 4 gene significantly increases the likelihood of developing Alzheimer’s disease. Now, a new study suggests that this gene pair isn’t just a risk factor but a genetic form of the disorder.
According to recent findings published in *Nature Medicine*, having two APOE4 genes makes it almost certain that you will develop Alzheimer’s, often with symptoms appearing at an earlier age. This stronger connection between APOE4 and Alzheimer’s suggests that different prevention and treatment strategies may be necessary.
So, what do these findings mean for your Alzheimer’s risk, and should you consider getting tested for the APOE4 gene? Neurologists Ayesha Sherzai, MD, and Dean Sherzai, MD, PhD, co-directors of the Alzheimer’s Prevention Program at Loma Linda University in California, provide some insights. The Sherzais, who also host the brain health podcast *Your Brain On*, explain:
Ayesha Sherzai: The APOE4 genotype primarily regulates lipid transport between cells. Certain fat molecules, essential for cellular infrastructure, chemical production, and internal functioning, need to be transported in and out of cells. The receptors on cells that facilitate this process are regulated by the APOE4 genotype.
Ayesha Sherzai: Yes, everyone has APOE genes, which can be APOE2, APOE3, APOE4, or a combination of these types. Some of these genes function very well. For instance, if you have one or two copies of APOE2, you’re less likely to experience issues with fat metabolism. APOE3 is neutral—it doesn’t significantly protect or harm you. However, APOE4 is less effective. If you carry one copy of APOE4, you’re more prone to lipid transport abnormalities, and if you have two copies, the impact is even more severe.v
Dean Sherzai: Genetics play a role in everything, from cholesterol levels and diabetes to high blood pressure and severe conditions like strokes, and Alzheimer’s is no different. Genetic factors significantly influence outcomes.
In Alzheimer’s, we know some genes are 100% penetrant, meaning if you carry them, you are very likely to develop the disorder. These genes include APP, PSEN1, and PSEN2. If you have any of these, you’re almost certain to develop Alzheimer’s before age 65, though lifestyle changes can delay its onset.
Previously, we believed APOE4 had a lower penetrance, around 50%, meaning about half of the people who live to 85 and carry two copies of APOE4 would develop the disease. However, this new study suggests that APOE4 might have a higher penetrance than we initially thought, indicating it has a stronger influence on whether someone develops Alzheimer’s.
Ayesha Sherzai: There are tests available to determine your genetic variation, including APOE status, but these tests are not commonly done in a clinical setting. Neurologists or primary care physicians typically do not order APOE testing, and it’s generally not covered by insurance.
However, you can pay out-of-pocket to have your genes tested through external companies. Whether you choose to do this is entirely up to you. If you have the financial means and want to know, you could consider getting it done.
Dean Sherzai: If someone has multiple family members with Alzheimer’s, there may be a case for testing. In such situations, some insurance companies might cover the cost, but it’s uncommon. The testing can be done through a blood test or a swab test, where they collect a sample of your saliva and send it to a lab
Mental activity is also a powerful protector as it helps connect neurons. With 87 billion neurons in our brain, each can form a few connections or as many as 30,000 to 50,000 connections. What makes the difference is exercise and mental stimulation. Staying engaged, challenging yourself, and pursuing your passions helps maintain these vital connections.
Ayesha Sherzai: We tend to only start thinking about our brain health when we hear the word “Alzheimer’s,” but we shouldn’t wait until a crisis or a certain age to consider it. Alzheimer’s doesn’t begin with the first signs of memory loss; the pathological changes in the brain start 20 to 30 years before any symptoms appear. For those of us in our 30s, 40s, and 50s, it’s essential to address risk factors now to ensure a healthy brain later on.
