Everyone carries two copies of the APOE gene, which makes a protein called apolipoprotein E (ApoE). There are three different types of the APOE gene, called alleles: APOE (epsilon) e2, e3 and e4 (or just E2, E3 and E4). Everyone has two copies of the gene so the combination determines your APOE "genotype”: either E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. The E2 allele is the rarest form of APOE and carrying even one copy appears to reduce the risk of developing Alzheimer's while the APOE3 allele is the most common and doesn't seem to influence the risk. The APOE4 allele, present in ~20% of the population, increases the risk for Alzheimer's. APOE4 alleles are the greatest genetic risk factor for late-onset Alzheimer's. However, this doesn't mean that you will absolutely get Alzheimer's disease if you have one or two copies of APOE4. Many people develop Alzheimer's who don’t have an APOE4 allele. It does, however, increase your risk for developing the disease as well as lower the age of potential disease onset.
APOE4 alleles are the greatest genetic risk factor for late-onset Alzheimer's. However, this doesn't mean that you will absolutely get Alzheimer's disease if you have one or two copies of APOE4. Many people develop Alzheimer’s who don’t have an APOE4 allele. It does, however, increase your risk for developing the disease as well as lower the age of potential disease onset.
When thinking about APOE and Alzheimer's disease risk, it is helpful to consider risk scores as relative to a risk of "1" for people with two alleles of APOE3. The table below illustrates the different estimated risks of developing Alzheimer's for people with different APOE genotypes relative to a disease risk of "1." For example, a risk of "3.2" for people with one APOE3 allele and one APOE4 allele means those people are 3.2 times more likely to develop the disease than people with two APOE3 alleles. Conversely, a risk score lower than "1" means a lower chance of developing Alzheimer's. People who have an APOE2 allele and no APOE4 allele are 40% less likely to develop Alzheimer's. However, new research suggests that the increased risk conferred by APOE4 alleles may be most important for women (read more about this finding in this Science Daily article.
To learn more about the genetics of Alzheimer's disease and the contribution of the APOE genes you can read the National Institute on Aging's Alzheimer's Disease Genetics Fact Sheet and the Mayo Clinic's pages on Alzheimer's genetics.
THE BIOLOGY OF APOE
Research has shown that the APOE protein plays many important roles in the body, including transporting cholesterol and cholesterol-like molecules, including beta-amyloid, in and out of cells. But the proteins made by different APOE alleles handle this transport function quite differently. In the case of beta-amyloid, whose transport out of the brain is mediated by APOE, APOE2 appears to be much better at clearing beta-amyloid than the APOE4 version, with APOE3 somewhere in the middle. This difference in beta-amyloid transport represents what scientists call "loss-of-function" toxicity. However, researchers also suspect that APOE4 proteins may also have toxic "gain-of-function" activities. For example, the presence of APOE4 appears to increase the formation of beta-amyloid plaques in the brain. The picture below illustrates examples of suspected "gain-of-function" and "loss-of-function" activities of APOE4.
APOE4 AND ALZHEIMER'S DRUG DISCOVERY
The Alzheimer's Drug Discovery Foundation (ADDF) is actively supporting many drug development programs to target APOE to prevent or treat Alzheimer's disease.
Some drugs-in-development may physically change the structure of the APOE4 protein to behave more like the APOE2 protein (called "structure correctors"). Other molecules can enhance the interactions between APOE4 and beta-amyloid, in hopes of increasing beta-amyloid clearance from the brain and preventing the potentially toxic effects of beta-amyloid accumulation and plaque formation. Another approach currently being tested in clinical trials is using modified viruses to deliver APOE2 genes into people who have APOE4 genes, potentially changing their genotype and lowering their risk of developing Alzheimer's disease or increasing their body's natural ability to fight the disease if they already have it.
To learn more about ADDF-supported drug development programs targeting APOE4, search our research portfolio with a filter for "APOE4."
EVIDENCE THAT APOE GENOTYPE IMPACTS THE EFFECTS OF POTENTIAL ALZHEIMER'S PREVENTION THERAPIES
Some scientific evidence exists to suggest that certain proposed Alzheimer's prevention therapies may work differently in people who carry at least one copy of the APOE4 gene. This section will highlight that information and link to our detailed reports of therapies where a differential effect is suspected. Please check back regularly for updates.
PREVENTIONS IDEAS THAT MAY BE MORE OR LESS EFFECTIVE IN APOE4 CARRIERS:
Estrogen: Several studies suggest that estrogen-containing hormone replacement therapy could have worse effects in people who carry the APOE4 allele, at least in terms of brain aging and dementia risk. However, the evidence is inconsistent.
Hypertension Management: Effective management of mid-life hypertension is likely though not proven to reduce the risk of dementia and cognitive decline in most people. APOE4 carriers might be particularly likely to receive this benefit from effective hypertension management, based on a handful of observational studies, but the complex relationships between cardiovascular health, APOE status and cognition are not yet understood.
DHA: May be part of a healthy diet for APOE4 carriers but evidence from observational studies, clinical trials, and some animal research suggests that DHA is particularly unlikely in APOE4 carriers to protect against dementia or cognitive decline.
Statins: Evidence is mixed if statins have different effects on brain health in people who carry at least one APOE4 allele: several observational studies found no effect on APOE4 allele status while two others suggested different effects cognition in patients with at least one APOE4 allele.
Nicotine: Although there is no evidence suggesting different Alzheimer's disease benefits from nicotine between APOE4 carriers and non-carriers, some evidence suggests nicotine may be a stronger accute cognitive enhancer in APOE4 carriers than non-carriers. To learn more, read our report on nicotine.
Cerebrolysin: One clinical trial compared the Exelon™ patch with Cerebrolysin found no differences in response rates in patients with at least one APOE4 allele but a 3-fold higher response rate in patients without an APOE4 allele.
Aaron Carman, PhD, was previously the Assistant Director of Aging and Alzheimer's Prevention at the Alzheimer's Drug Discovery Foundation. Dr. Carman received his doctorate in microbiology and molecular genetics from The University of Texas Health Science Center at Houston.
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