Genetic Testing & APOE4 for Alzheimer’s Risk
Genetics can influence a person’s risk of developing Alzheimer’s disease. The most important common genetic risk factor is APOE4, which can be identified through a blood or saliva test. Having one copy increases risk; having two copies increases it considerably more. But APOE4 is not a diagnosis—many people who carry it never develop Alzheimer’s.
Knowing your APOE status may help you better understand your risk and pay greater attention to potentially modifiable factors such as exercise, metabolic and cardiovascular health, diet, sleep, and other lifestyle choices. Genetic testing can also have psychological and family implications, so some people may prefer to discuss testing with a physician or genetic counselor.
The most important message is simple:
Genetic risk is not destiny.
Understanding APOE
Everyone inherits two copies of the APOE (apolipoprotein E) gene—one from each biological parent. APOE helps the body transport cholesterol and other fats and also plays important roles in the brain.
There are three common forms:
APOE2 — relatively uncommon and generally associated with a lower risk of Alzheimer’s.
APOE3 — the most common form and generally considered neutral for Alzheimer’s risk.
APOE4 — associated with an increased risk of late-onset Alzheimer’s disease.
People can therefore have combinations such as APOE2/3, APOE3/3, APOE3/4, or APOE4/4. Having one APOE4 copy increases risk, while inheriting two copies increases risk substantially more.
APOE4 is a risk factor, not a cause or diagnosis. Some people with APOE4 remain cognitively healthy throughout life, while many people who develop Alzheimer’s do not carry APOE4.
How Much Does APOE4 Increase Your Risk?
APOE4 can substantially increase the likelihood of developing Alzheimer’s disease, but it cannot predict with certainty what will happen to an individual.
Having one copy of APOE4 increases risk, while having two copies (APOE4/4) increases risk considerably more. APOE4 is also associated with developing Alzheimer’s at an earlier average age.
Recent research has drawn particular attention to people with two APOE4 copies. Studies have found that a very high proportion develop Alzheimer’s-related biological changes in the brain as they age. However, having these biological changes is not the same as developing dementia, and not everyone with APOE4/4 develops Alzheimer’s symptoms.
Risk also varies according to ancestry, sex, age, other genes, cardiovascular and metabolic health, and lifestyle and environmental factors. Some APOE4 carriers live into old age without developing dementia.
APOE4 does not determine your future. Genetic testing provides information about risk, not a prediction of whether or when an individual will develop Alzheimer’s.
Should You Get Tested?
A simple blood or saliva test can determine your APOE status. But whether a healthy person should be tested is still debated.
Genetic testing is not routinely used to predict Alzheimer’s disease in people without symptoms. The test cannot tell you whether you will develop Alzheimer’s, and learning that you carry APOE4 can cause anxiety or worry.
There are also reasons someone may choose to know. APOE status can provide a clearer picture of genetic risk and may encourage greater attention to exercise, blood pressure, metabolic health, diet, sleep, and other potentially modifiable risk factors. It may also be useful for participation in research studies.
APOE testing has become increasingly important for people considering newer anti-amyloid Alzheimer’s drugs. APOE4 carriers—particularly people with two copies—have a higher risk of ARIA, a potentially serious side effect involving brain swelling or bleeding.
For someone without symptoms who wants testing primarily for prevention, it is worth discussing the advantages and disadvantages with a physician or genetic counselor before deciding.
If You Have APOE4, What Can You Do?
You cannot change your genes, but you can address many factors associated with cognitive decline. Having APOE4 may be an additional reason to pay attention to brain, metabolic, and cardiovascular health.
Important steps include regular aerobic and strength exercise, maintaining healthy blood pressure and blood glucose, getting adequate sleep, avoiding smoking, staying socially and mentally active, addressing hearing loss, and eating a nutrient-rich diet.
Researchers are also studying whether APOE4 carriers may benefit from more individualized approaches to diet, cholesterol management, omega-3s, and other interventions. The evidence for APOE4-specific strategies is still developing.
Some physicians, including Dr. Dale Bredesen, use APOE status as part of a more personalized approach to Alzheimer’s prevention.
Karin Dee — APOE4 & Alzheimer’s Prevention
Karin Dee is the founder of Brain Health Science, where she writes about APOE4 and Alzheimer’s prevention. She follows research on genetics, metabolic and cardiovascular health, nutrition, exercise, sleep, biomarkers, and other factors that may influence brain health. Her central message is that while APOE4 increases Alzheimer’s risk, it does not make Alzheimer’s inevitable.
A practical introduction for people who have recently learned that they carry APOE4. Dee discusses laboratory testing, genetics, diet, exercise, sleep, metabolic and cardiovascular health, omega-3-rich fish, and selected supplements.
Dee summarizes the strategies she considers most important for reducing Alzheimer’s risk, especially for APOE4 carriers. They include metabolic health, exercise, sleep, DHA-rich fish, mild ketosis, and selected supplements. She emphasizes addressing multiple risk factors and making changes gradually.
Dee examines emerging research on vitamin C and brain health. Her emphasis is not on megadosing vitamin C, but on avoiding deficiency and getting the fundamentals right.
Rare Genes That Can Cause Alzheimer’s
APOE4 is a risk gene, but rare pathogenic variants—primarily in APP, PSEN1, and PSEN2—can cause inherited forms of Alzheimer’s disease. These usually lead to early-onset Alzheimer’s, often before age 65, and tend to run strongly through generations of a family.
They account for only a small fraction of all Alzheimer’s cases. Testing for these variants is generally considered when there is an unusually early onset or a strong family history of early-onset Alzheimer’s.
Learn More
A clear overview of APOE2, APOE3, APOE4, genetic testing, and the rare genes that can cause Alzheimer’s disease.
A reader-friendly explanation of APOE4, inherited risk, and genetic testing.
For readers who want more detail. This NIA workshop includes presentations by leading APOE researchers on APOE4, ancestry, amyloid, brain biology, and potential treatments.
Videos
A short explanation of APOE4 risk and approaches Bredesen recommends for reducing that risk.
Dr. Norwitz, who carries two copies of APOE4, discusses his increased genetic risk for Alzheimer’s and the diet, exercise, metabolic health, and other lifestyle strategies he uses in an effort to reduce that risk.