Should You Get Tested for the Genetic Variant Linked to Alzheimer's Disease?

There is recent evidence suggesting a direct genetic link in some cases of Alzheimer's, prompting considerations for the future of diagnosis and treatment.

At present, an identifiable underlying cause for most Alzheimer's cases is elusive. Yet for long, scientists were aware that inheriting a copy of the gene variant APOE4 could increase the probability of a diagnosis. Individuals with two copies, constituting 2-5% of the general population, face an amplified risk.

However, there is a new proposal from researchers stating that possessing two APOE4 copies might not only heighten disease development risk but cause it.

"This broadens our perception to include 15 to 20% of cases that can be genetically accounted for," noted Juan Fortea, PhD, leader of the study from Sant Pau Research Institute in Barcelona, Spain. "This is vital for facilitating specific research and interventions, enhancing our understanding of the foundational mechanisms of the disease."

The published findings in the Nature Medicine journal suggests more individuals may get an Alzheimer's diagnosis before symptoms appear. Medical professionals are optimistic that this research will ignite the formulation of treatments and start targeted clinical trials regarding this demographic.

"Our results represent more than scientific advancement," Fortea stated. "They are a stride towards converting optimism into actionable strategies for those impacted by Alzheimer's."

The following is a pointer to how scientists made the discovery, the potential implication for Alzheimer's treatment, and whether experts recommend testing for the presence of the genetic variant.

The study involved scrutinizing data from 3,297 brain donations for medical research and 10,000 individuals partaking in Alzheimer's studies in the US and Europe.

A total of 273 individuals had two copies of APOE4. Almost all exhibited Alzheimer's signs in their brains. The study thus deduced that owning two APOE4 copies should be regarded as a genetic manifestation of Alzheimer’s.

The researchers also noticed that patients developed Alzheimer's pathological changes relatively early.

By the age of 55, subjects with two APOE4 copies accumulated more amyloid, associated with Alzheimer markers, than those with a single copy of another APOE variant—the APOE3 allele. Almost all had unconventional amyloid levels by age 65, and many commenced experiencing Alzheimer's symptoms at 65, which is earlier than most individuals without the APOE4 variant.

"The research beautifully illustrates that possessing two APOE4 gene copies predictably results in pathological brain changes in almost every carrier," stated Jim Ray, PhD, Belfer Neurodegeneration Consortium director at MD Anderson Cancer Center who wasn't involved in the study.

Fortea admitted certain limitations in the study. For instance, nearly all the participants were White, and, given that APOE-associated risk varies among different ethnicities, the findings might not be universally applicable.

Ray and other experts believe the research could stimulate the creation of new drug treatments for people with the two gene variant copies—both pre and post symptom manifestation.

"The study strongly suggests the need for therapeutics targeting the APOE4 gene for the millions at risk for AD," he commented.

There is presently no known cure for Alzheimer's, although certain drugs may temporarily alleviate symptoms.

Leqembi, which helps break down brain amyloid, is a standard prescription. Hesitancy to prescribe it broadly exists due to its FDA-mandated black-box warning, indicating potential "grave and life-threatening events" such as bleeding and brain swelling, particularly with individuals carrying two APOE4 copies.

"We are on the brink of an era marked by the arrival of disease-modifying treatments, which holds immense promise for those with genetic markers related to Alzheimer's," Fortea added.

The latest study prompts the question of whether asymptomatic individuals should undergo testing to assess if they carry two APOE4 copies.

Those with both parents diagnosed with Alzheimer's relatively early on—probably in their 60s—are the most probable carriers of the two APOE4 genes.

Currently, routine use of genetic tests for Alzheimer's diagnosis or risk prediction in clinical settings does not occur. Many experts counsel against it due to the complexities in result interpretation.

Fortea doesn’t believe the new study should alter any testing guidance.

“At this stage, our findings do not advocate for changes in testing practices for Alzheimer’s,” Fortea said. “More research is needed, particularly in developing preventive treatments and accurately assessing risk, before we can offer concrete recommendations for genetic testing or counseling in the context of these findings.”

If you are curious about whether you have one or two copies of the APOE4 gene or concerned that you might, consult a doctor or genetic counselor about whether testing might be right for you.