Information about Proteins that May Increase Alzheimer's Risk

Apolipoprotein E

Several Alzheimer's studies have focused on a protein called apolipoprotein E (APOE), which appears to play a role in the formation of amyloid plaques. APOE is one of the lipoproteins that carry cholesterol and other fats in the blood. The gene that directs the production of APOE is located on chromosome 19. It exists in three different versions, known as alleles: APOE ε2, APOE ε3, and APOE ε4.

Every person carries two APOE genes, one inherited from each parent. Therefore, an individual can have any one of six combinations of these alleles: either a mixed set (for example, ε2/ε4) or a matched pair (for example, ε4/ε4).

Different alleles appear to confer different risks for the development of Alzheimer's disease. People who inherit the relatively rare APOE ε2 form appear to be at lower risk for Alzheimer's than others, and if they do develop the disease, the age of onset is usually later.

APOE ε3 is the most common variety (half the general population is ε3/ε3). Researchers believe this allele plays a neutral role in the risk of Alzheimer's disease.

APOE ε4, however, is associated with an increased risk or earlier onset of Alzheimer's. Individuals with one copy of APOE ε4 have a three times greater risk of developing Alzheimer's than those without APOE ε4. A person with two copies of APOE ε4 (approximately 3% of the white population) has a 50% chance of developing Alzheimer's disease by age 80.

How APOE ε4 increases a person's susceptibility to Alzheimer's disease is not yet known. One theory is that its protein product binds quickly and tightly to beta-amyloid, making it more insoluble. (As mentioned previously, insoluble beta-amyloid fragments build up and form plaques—a hallmark of Alzheimer's.)

APOE ε4 also appears to speed up the Alzheimer's process and lower the age of onset. The average age of onset for Alzheimer's symptoms is 84 among people with no copies of APOE ε4, 75 in those with one copy, and 68 in those with two copies. Increased risk, however, does not guarantee illness, and the presence or absence of APOE ε4 in a blood sample cannot predict who will get Alzheimer's.

A person can have APOE ε4 and never get the disease. For example, a woman in the Nun Study who died at age 107 had one copy of the APOE ε4 allele but was highly functional until she died.


A protein known as lipoprotein(a) may play a role in encouraging the APOE protein to bind to and enter neurons. In one study, elevated levels of lipoprotein(a) increased the risk of late-onset Alzheimer's among carriers of the APOE ε4 allele. In people over age 80, those with the APOE ε4 allele and high levels of lipoprotein(a) had a six times greater risk of Alzheimer's than those with lower levels.

Conversely, in noncarriers of the APOE ε4 allele who were over age 80, those with high levels of lipoprotein(a) had a 60% lower risk of Alzheimer's disease.

Publication Review By: Peter V. Rabins, M.D., M.P.H.

Published: 10 Mar 2011

Last Modified: 23 Jun 2011