What is the APOE gene and what is its significance for Alzheimer’s disease?

The APOE gene is one of over 20,000 genes that comprise the human genome. Three alleles (or variants) of the APOE gene are common and identified as APOE ∑(sigma) 2, APOE ∑3, and APOE ∑4.

The primary function of the APOE gene in the human body is regulation of lipids through expression of the apolipoprotein, (APOE). APOE expression in the brain is instrumental in regulating the prevention of cellular damage that can lead to Alzheimer’s disease (such as weakening of cellular membranes in the brain, or damage to the blood-brain barrier), and critical to processes that clear out pathologies associated with Alzheimer’s disease, such as accumulation of amyloid-beta protein plaques and tau protein tangles.

Inherited combinations of the three common APOE alleles create differing risks for the onset and progression of Alzheimer’s disease.

Each person inherits two copies of common genes, one each from father and mother. Varying copy combinations of the APOE gene appear to influence the likelihood that an individual will develop Alzheimer’s disease, and the rate at which the disease will progress.

• The APOE ∑3 allele is by far the most common genetic variant of APOE. Individuals with two copies of APOE ∑3 are thought to have an average risk for development of Alzheimer’s disease. Average lifetime risk of Alzheimer’s disease for adults aged 45 in the U.S. has been estimated at 20 percent for women and 10 percent for men.
• Conversely, the APOE ∑2 allele and APOE ∑4 alleles are rare. Individuals with one or two copies of the APOE ∑2 allele appear to have a genetic “protective punch “ that reduces risks for Alzheimer’s, while individuals with one or two APOE ∑4 copies have increased risk.

Alzheimer’s risks attributable to APOE genes vary according to the combination of these genes in each individual

A recent study (Khajouei 2025) identified the prevalence of varying APOE gene combinations among 180,000 persons of diverse ethnic-genetic backgrounds who are contributors to the National Institute of Health’s All of Us research database of personal health information.  A separate analysis (Williams 2025) attributed the prevalence of Alzheimer’s disease to APOE copy variations among participants in four large studies has attributed.  An overlay of results from both initiatives results in the following approximations.

*Lifetime risks of Alzheimer’s disease among persons with the APOE2/APOE2 combination may be as low as 1-2 percent.  ( See Reiman, et al 2020, for background)

Implications of APOE status for Alzheimer’s disease prevention and health care

Alzheimer’s Disease Prevention:  While APOE ∑3 and APOE ∑4 status conveys increased risk of Alzheimer’s disease to individuals, actual onset of the disease is still uncertain and depends upon multiple factors. Recurring evidence reviews from The Lancet Standing Commission on Dementia suggest that upwards of 40 percent of Alzheimer’s cases are due to causes that are preventable or modifiable, including diet, physical activity, social determinants of health and environmental factors. Recent findings from the POINTER (Protect Brain Health Through Lifestyle Interventions to Reduce Risks) study indicate that structured interventions encompassing healthy diet, increased physical activity and cognitive challenge and social engagement can result in measurable improvements in cognition and memory among individuals at risk for cognitive impairment and dementia. Improvements appear to be present across all varying combinations of APOE alleles, including APOE ∑4 combinations.

 Early Detection of Alzheimer’s Disease: At present APOE genetic testing is not an evidence-based screening practice. However, the increasing evidence on APOE-associated risks of Alzheimer’s disease may prompt new thinking on testing as a preventive health measure that could risk-stratify patients for susceptibility to Alzheimer’s disease and triage patients for periodic monitoring by cognitive assessment and biomarker testing. For example: individuals with APOE ∑2/∑2 or APOE ∑2/∑3 status might be triaged to less intensive monitoring, while individuals with APOE ∑3/∑4 or APOE ∑4/∑4 status might be triaged to more intensive monitoring and intensified prevention measures.

 APOE-associated risks of adverse events from disease modifying therapy (DMT): Individuals carrying one or two copies of APOE ∑4 genes appear to be at greater risk for pathologies in the brain that can be exacerbated by anti-amyloid, disease-modifying therapies for early Alzheimer’s disease. For example: APOE-associated risks include both increased proclivity for growth of amyloid plaques and tau tangles, and decreased ability for the brain to clear these toxic concentrations due to weakened integrity of brain cells and blood-brain barrier. The primary risk created with DMT administration is brain hemorrhaging signaled by amyloid-related imaging abnormalities (ARIA-H). Evidence from real world administration of anti-amyloid therapies thus far suggests overall levels of ARIA-H may range from 17-31 percent of treated patients, symptomatic ARIA-H is relatively uncommon, in the 0.6- 0.7 percent range for lecanemab (Leqembi/Eisai-Biogen) and donanemab (Kisunla/Eli Lilly). Currently, patients treated with lecanemab or donanemab are monitored for ARIA-H as a requirement of FDA-approval of the drugs.

Patient outcomes from anti-amyloid disease modifying therapies: The clinical trials of the two FDA-approved anti-amyloid therapies (lecanemab and donanemab) did not exclude participants on the basis of APOE status. However, the varying safety risks faced by individuals with higher-risk APOE status (such as APOE ∑3/∑4 or APOE ∑4/∑4) suggest that the net benefit of treatment may vary as well and remains subject to evaluation from real world evidence.

Challenges for Detection, Diagnosis and Treatment of Early Alzheimer’s Disease Associated with APOE

Strengthening evidence on the role of APOE status on risks of Alzheimer’s onset and progression pose numerous challenges --- and opportunities – for improving prevention or mitigation of Alzheimer’s disease while delivering prevention and medical care more efficiently and at greater scale.

Among the challenges:

Determining effective policies for APOE genetic testing at the population level: Abnormal amyloid concentrations are known to accumulate in the brain years before Alzheimer’s disease symptoms may occur. Early APOE screening to determine higher-risk individuals could serve to trigger early interventions (prevention measures, early monitoring for detection of pre-symptomatic Alzheimer’s disease) and identify patients most likely to benefit from disease-modifying therapies. Recent studies suggest that 25 percent or more adults are at elevated risk for eventual onset of Alzheimer’s disease due to APOE status, (see table above.)

Refining disease modifying therapy regimens and risk management by APOE status: APOE status influences risks for Alzheimer’s onset, rate of progression, and adverse events from DMT administration. As noted above, this also suggests APOE status may affect the level of benefit from DMT treatment. Collection of robust, longitudinal real world evidence (RWE) is necessary to determine how DMT administration can be optimized.

Potential for genetic therapy to prevent or arrest onset of early Alzheimer’s disease: Evidence that one genetic variant of the APOE gene, the APOE ∑2 allele, suggests that gene editing or other genetic modification techniques might lead to development of genetic medicines to avert or modify Alzheimer’s disease, such as medicines to introduce the protective effects of APOE ∑2 status.

Learn More

Alzheimer’s Association, “Is Alzheimer’s Genetic?”, Alzheimer’s Association Fact Sheet

Kaiser J, “The Burden of a Gene,” Science , September 12, 2024

National Institute on Aging, Alzheimer's Disease Genetics Fact Sheet

National Institute on Aging Research Highlights, “APOE ε2 gene variant packs protective punch against Alzheimer’s disease,”  May 7, 2020

National Institute on Aging Research Highlights, “Study reveals how APOE4 gene may increase risk for dementia,”  March 16, 2021