Genes are one of many risk factors for dementia. While a quarter of Alzheimer's patients have a strong family history of the disease, only 1% directly inherit a gene mutation that causes early-onset Alzheimer's, also known as familial Alzheimer's disease (FAD) [1]. But another gene called APOE can influence your risk for the more common late-onset type of Alzheimer's.
There are three types of the APOE gene, called alleles: APOE2, E3 and E4. Everyone has two copies of the gene and the combination determines your APOE "genotype"—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 by up to 40%. APOE3 is the most common allele and doesn't seem to influence risk. The APOE4 allele, present in approximately 10-15% of people, increases the risk for Alzheimer's and lowers the age of onset. Having one copy of E4 (E3/E4) can increase your risk by 2 to 3 times while two copies (E4/E4) can increase the risk by 12 times [2].
Despite this association, the National Institutes of Health only recommends genetic testing for APOE status to advance drug research in clinical trials. APOE4 is just one of many risk factors for dementia and its influence can vary across age, gender, race, and nationality [3][4]. For example, having one copy of the E4 allele may pose more risk to women while having two copies seems to affect men and women similarly [5].
To learn more about the genetics of Alzheimer's disease and the contribution of the APOE genes, check out the National Institute on Aging's Alzheimer's Disease Genetics Fact Sheet.
The APOE protein plays many important roles, including the transport of cholesterol across different tissues and cells. The proteins made by varying APOE alleles handle this transport function differently.
Outside the brain, APOE4 can increase the risk of atherosclerosis (i.e., hardening of the arteries) and stroke [4], which may explain why APOE4 is a risk factor for vascular causes of cognitive impairment and dementia [6][7]. Inside the brain, APOE helps to clear beta-amyloid, a component of plaques. APOE2 appears to perform this function more effectively than APOE4, with APOE3 in the middle. This difference in beta-amyloid transport represents what scientists call "loss-of-function" toxicity. However, researchers suspect that APOE4 proteins may also have toxic "gain-of-function" activities, such as increased response to stress or injury [4].
APOE4 may increase the risk of dementia through toxic gain of function and through the loss of normal healthy function. Figure adapted from [4]
Some drugs in development (called "structure correctors") may change the physical structure of the APOE4 protein so that it behaves more like the APOE2 protein [8]. Another approach is gene therapy, which attempts to insert APOE2 genes into the brains of people with APOE4 genes [9]. To learn more about these programs and other APOE-related drug discovery programs supported by the Alzheimer's Drug Discovery Foundation, review our research portfolio with a filter for "APOE4."
Researchers are exploring whether the APOE genotype influences the effects of drugs and other therapies in development for Alzheimer's disease and general cognitive health. Highlights of the scientific research in which a differential effect is possible follows, with links to reports.
Estrogen: Several studies suggest that the side effects of estrogen-containing hormone replacement therapy may be worse 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 to reduce the risk of dementia and cognitive decline in most people. Observational studies suggest that APOE4 carriers might be particularly likely to reap the benefits of effective hypertension management. However, the complex relationships between cardiovascular health, APOE status, and cognition are not well understood.
DHA: Although DHA may be part of a healthy diet for APOE4 carriers, evidence from observational studies, clinical trials, and some preclinical research suggests that it is less likely to protect against dementia or cognitive decline in APOE4 carriers. Some researchers are testing the idea that APOE4 carriers simply need higher doses of DHA because it does not reach their brains as effectively [10].
Statins: Evidence is mixed on whether statins have different effects on brain health in people who carry at least one APOE4 allele. Several observational studies found that APOE4 allele status had no effect while another suggested different effects on 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 acute cognitive enhancer in APOE4 carriers than non-carriers.
Cerebrolysin: One clinical trial comparing the Exelon™ patch with cerebrolysin found no difference in response rates in patients with at least one APOE4 allele but a 3-fold higher response rate in patients without an APOE4 allele.
Dr. Penny Dacks was previously the Director of Aging and Alzheimer’s Disease Prevention at the Alzheimer's Drug Discovery Foundation. She was trained in neuroscience at the Mount Sinai School of Medicine, the University of Arizona, and Queen's University (Canada) with individual fellowships from the National Institute of Health, the Evelyn F. McKnight Brain Research Foundation, the ARCS Foundation and the Hilda and Preston Davis Foundation. She has authored over 18 peer-reviewed scientific articles and is a member of the Society for Neuroscience, the Gerontological Society of America, the Endocrine Society and the Association for Women in Science.
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