One of the strongest genetic risk factors for developing Alzheimer’s is a genetic variant of the apolipoprotein E gene, called ApoE4. One in four people in the population carry one copy of this variant, while one in 50 carry two copies. 

Although people with two copies of the gene are rare in the population, this small group accounts for one in six Alzheimer’s cases. This said, carrying the ApoE4 gene does not mean Alzheimer’s is inevitable. One copy of the gene means a 15- to 20-percent chance of Alzheimer’s at some point during a person’s lifespan, while two copies increase the risk to 60 percent. 

In addition to increasing the risk of developing the disease, the ApoE4 gene also increases the risk of certain side effects—brain swelling and brain bleeding events called ARIA—for people taking new monoclonal antibody drugs for Alzheimer’s. Many doctors now run a genetic test to help assess a person’s risk of side effects before prescribing drugs like Kisunla or Leqembi. 

What does the APoE gene do, and why does APoE4 increase the risk of Alzheimer’s?

The ApoE gene gives instructions to a protein that carries fats and cholesterol throughout the brain, which both keep brain cells healthy and functioning. The protein instructed by the ApoE4 variant holds onto cholesterol more tightly than proteins instructed by other variants of the gene, like ApoE3 or ApoE2. 

Scientists think that APoE4 can make the brain more vulnerable to Alzheimer’s by holding on to cholesterol rather than delivering it to where it is needed. People with two copies of the ApoE4 variant experience a sequence of changes in the brain—an increase in amyloid and tau—and shrinkage of the hippocampus, which is important for memory, similar to Down syndrome and genetic forms of Alzheimer’s. 

As a result, some researchers have even proposed that people carrying two copies of the APoE4 gene may have a unique genetic form of Alzheimer’s, which may require a unique treatment.

Alzheimer’s treatments for people carrying the APoE4 gene

Since APoE4 carriers experience more side effects from certain Alzheimer’s drugs, drugmakers are developing treatments specifically for them. Alzheon is completing a Phase 3 trial of its Alzheimer’s pill (valiltramiprosate) in patients with two copies of the APoE4 gene. The drug stops healthy forms of beta-amyloid from clumping into toxic plaques. The company expects to present results by the end of the year. Lexeo Therapeutics is in the early stages of testing a new genetic therapy to see whether it can edit out the risk by turning the ApoE4 variant into ApoE2, which doesn’t pose an increased risk of Alzheimer’s disease.

Meanwhile, other researchers are studying the brains of people with ApoE4 to see how protein levels in the brain change before the onset of symptoms. Scientists then use the clues from these studies to zero in on new potential treatment targets.