APOE4 Gene Targeted in Multiple Alzheimer's Treatment Approaches
Multiple therapeutic approaches targeting the APOE4 gene are advancing, including small molecule drugs, gene therapies, and repurposed medications. The APOE4 variant confers a 60% lifetime Alzheimer's risk and affects brain metabolism, increasing seizure susceptibility. Research shows blood pressure drug terazosin can reduce seizures in APOE4 models by boosting cellular energy production.
Scientists are pursuing multiple therapeutic strategies targeting the APOE4 gene, which significantly increases Alzheimer's disease risk and affects brain function in several ways. People who carry two copies of the APOE4 gene have a 60 percent lifetime risk of Alzheimer's disease, and they represent one in every six Alzheimer's patients despite comprising only 2 percent of the general population.
The APOE4 variant leads to changes in the brain's immune system and metabolism, making the brain more vulnerable to the build-up of beta-amyloid, tau, and inflammation later in life. While there are two FDA-approved anti-amyloid therapies, not everyone who carries the APOE4 gene can take them because those with two copies have an increased risk of amyloid-related imaging abnormalities (ARIA) — brain swelling and small brain bleeds.
Small molecule drugs that target APOE4 biology are considered attractive because they could be given by pill rather than infusion or injection. Alzheon ran a Phase 3 trial testing an experimental pill called valiltramiprosate exclusively in people with two copies of the APOE4 gene, though it failed in its Phase 3 trial of mild cognitive impairment and early Alzheimer's in 2025. The company hasn't given up on the treatment and will run an additional trial looking at mild cognitive impairment.
Other approaches include bumetanide, a drug approved to treat fluid retention that's being tested in a small Phase 2 Alzheimer's trial, and CS6253, a small peptide being developed by Artery Therapeutics that binds to a protein called ABCA1 to enhance beta-amyloid clearance from the brain. The Alzheimer's Drug Discovery Foundation is funding early-stage research to develop a pill that acts as an APOE4 corrector, changing the behavior of the protein so it behaves more like the lower-risk version, APOE3.
Gene therapies represent another frontier. Lexeo Therapeutics is developing multiple gene therapies that insert the DNA for the protective APOE2 variant into the brain. The company completed an early stage trial of LX1001, which involves injecting a virus carrying the protective gene into the spinal canal. They are also developing LX1021, a similar gene therapy that inserts a version of the APOE2 gene called the Christchurch mutation that confers even stronger protections. Their other candidate, LX1020, delivers the protective APOE2 gene alongside small bits of genetic material that would suppress the APOE4 gene.
Switch Therapeutics will soon head to early-stage trials for its APOE4-silencing gene therapy designed to bypass the liver, where APOE serves a crucial role, to reduce the risk of side effects.
A new study has revealed additional mechanisms by which APOE4 affects brain function. Researchers found that the APOE4 gene boosts seizure activity by decreasing levels of ion pumps and energy-producing enzymes in neurons. Seizures are very prevalent symptoms of Alzheimer's disease patients: 10–22 percent experience unprovoked seizures, while up to 50 percent show subclinical epileptic activity, or hyperactivity in the brain. The APOE4 gene increases the risk of developing Alzheimer's disease twelvefold compared to the normal APOE3 gene.
The study found that mice with the human APOE4 gene began to have more seizures and seizure-induced deaths between 5.5 and 7 months of age, roughly equivalent to a human in their 30s. Female mice with both APOE4 and tau tangles had more severe seizures, though the presence of tau tangles did not make a difference for male mice.
Researchers discovered reduced levels of the sodium and potassium ion pump that regulates neuron activity in the hippocampus, the main brain region affected by Alzheimer's disease. They also found that both ATP and the enzymes that produce it during metabolism were in low supply in the hippocampi of APOE4 mice compared to those with the APOE3 gene.
To increase ATP levels, researchers treated the mice with the drug terazosin, a clinically available blood pressure drug that has been recently found to increase the ATP-making enzymes. Terazosin treatment increased ATP levels in the hippocampus and decreased seizure activity in the APOE4 mice, as well as the female mice with both APOE4 and tau tangles. The researchers then combined terazosin with an inhibitor that makes sure glucose in neurons is converted to the next step of the ATP-making metabolic pathway rather than converted to lactose, as can happen during brain hyperactivity or seizures. This combination further enhanced ATP levels and suppressed seizure activity.