APOE-ε4 Introduction


Having the APOE ε4 variant is a risk factor and does not mean you will get any disease associated with it. There are homozygous APOE ε4 carriers who, even at age 80, do not possess any symptoms of dementia or any other disease associated with the ε4 variant.


Alzheimer’s disease is a progressive neurodegenerative condition characterized by a decline in thinking and reasoning skills. People with Alzheimer’s are eventually unable to perform activities associated with daily living. It is the most common form of dementia in people over the age of 65; about one in 10 people over age 65 has Alzheimer’s disease and nearly half of all people over age 85 are affected.

Symptoms and Disease Progression

The earliest symptom of Alzheimer’s is subtle memory loss, especially difficulty remembering recently learned information. Other memory problems include difficulty finding words, not knowing common facts such as the name of the current president of the United States, and disorientation such as getting lost in one’s own neighborhood. Other symptoms of Alzheimer’s include problems performing familiar tasks such as brushing one’s teeth, difficulty in planning and managing tasks such as paying bills and grocery shopping, unpredictable mood swings, lack of motivation, and personality changes.

The exact mechanism of Alzheimer’s is unknown, but involves the accumulation of protein plaques and tangles in the brain over a time period of many years. As the plaques and tangles accumulate in the brain, nerve cells lose the ability to communicate with each other and eventually die, leading to progressive loss of memory and cognitive function. As nerve cells die off, brain tissue also shrinks, becoming most pronounced by the final stage of Alzheimer’s.

Diagnosis and Treatment

Alzheimer’s often goes unrecognized in its early stages because of the subtlety of its symptoms during this time and difficulty distinguishing these symptoms from normal aging. Alzheimer’s can be definitively diagnosed only after death and microscopic examination of brain tissue for changes characteristic of Alzheimer’s. However, physicians can diagnose Alzheimer’s fairly accurately based on a patient’s constellation of symptoms and by running blood tests and/or brain scans to rule out other potentially treatable causes of dementia. Recent advances in brain imaging have made it possible to detect protein plaques directly, potentially making early diagnosis more routine.

Although there is no cure for Alzheimer’s, there are medications that help some people with Alzheimer’s manage symptoms for a period of time. Treatment is targeted at cognitive, or thinking, problems as well as behavioral and psychiatric problems. For cognitive problems, several medications are available that target chemical messengers in the brain involved in Alzheimer’s. These medications are not without side effects, but can help maintain cognitive skills.

Behavioral and psychiatric problems can be managed without medication by implementing environmental changes and strategies to help the Alzheimer’s patient with daily activities and avoid stressful situations that can precipitate behavioral problems. When necessary, antidepressant, antipsychotic, and anti-anxiety medications can be used to manage behavioral and psychiatric problems.


Alzheimer’s disease is a neurodegenerative condition characterized by a decline in thinking and reasoning skills. People with Alzheimer’s are eventually unable to accomplish even the simplest tasks. The most common cause of dementia in people over 65, Alzheimer’s currently affects more than five million people in the United States. As the population ages, many more people are expected to develop Alzheimer’s; some estimate 14 million Americans will have the disease by the year 2050. The ε4 variant of APOE is the strongest genetic risk factor for late-onset (after the age of 65) Alzheimer’s.

The APOE gene encodes the protein apolipoprotein E, a cholesterol carrier that is found in the brain and other organs. However, the protein’s exact role in the development of Alzheimer’s is unclear. Several studies have shown that it may be involved in amyloid beta aggregation and clearance, influencing the onset of amyloid beta deposition that is believed, along with other factors, to ultimately lead to Alzheimer’s.

The ε4 variant is also a major risk factor for Alzheimer’s disease in African Americans and individuals of East Asian ancestry. Compared to average risk for these ancestry groups, one copy of the ε4 variant is associated with 1.5 times higher odds of developing Alzheimer’s in African Americans and 4 times higher odds in East Asians. Having two copies is associated with about 4 times higher odds in African Americans and 12 times higher odds in East Asians.

The Alzheimer’s Association estimates that elderly African Americans are more than twice as likely to develop Alzheimer’s disease compared to elderly Caucasians. It is unclear whether this disparity is primarily due to genetic or environmental factors. Several studies have shown, however, that the ε4 variant is more common in African Americans than in individuals of European or East-Asian ancestry, showing that genetics plays a role.

Having a copy of the ε4 variant of APOE does not mean that a person will definitely develop Alzheimer’s. Most people who have the ε4 variant never develop Alzheimer’s and more than half of the people with Alzheimer’s have no copies of APOE ε4 at all. But people with one copy of APOE ε4 who do get Alzheimer’s tend to get it earlier than patients with no copies of ε4 and people with two copies of APOE ε4 tend to get Alzheimer’s earlier still.

Risk for Alzheimer’s changes significantly with age

Most people who develop Alzheimer’s are diagnosed after age 80. In fact, the number of people who are diagnosed with Alzheimer’s doubles between age 79 and age 84, and doubles again between age 85 and age 90. Keep in mind that the risk estimates provided in this report are calculated up to age 80 (the approximate average life expectancy in the U.S.).

In contrast, residual risk, or the risk of developing Alzheimer’s by a certain age starting at one’s current age, decreases as an individual gets older. If an individual has reached a specific age—such as 70—without developing Alzheimer’s, his or her remaining risk for developing Alzheimer’s by age 80 will be lower than his or her lifetime risk would have been at age 50.

Family history is also a significant risk factor for Alzheimer’s disease

Although the APOE ε4 variant is the single strongest genetic risk factor for late-onset Alzheimer’s, having a first-degree relative (such as a parent or sibling) with Alzheimer’s can also more than double an individual’s risk of developing Alzheimer’s. Individuals with a first-degree relative with Alzheimer’s are at higher risk of developing Alzheimer’s if that relative has the APOE ε4 variant.

APOE variant frequencies

Genotype European African American East Asian
ε2/ε2 0.3% 0.4% 0.2%
ε2/ε3 10.8% 13.3% 7.9%
ε3/ε3 57.4% 41.7% 74.6%
ε2/ε4 2.2% 2.4% 0.9%
ε3/ε4 24.0% 34.1% 15.4%
ε4/ε4 2.9% 3.6% 1.0%

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