Researchers identify new genetic form of Alzheimer’s that is present in millions of people

A study published today raises a question with scientific, medical, ethical and even philosophical implications: if you could find out that you were going to develop Alzheimer’s disease at age 65 with almost 100% probability, would you want to know? Would you live your life differently?

A study published on Monday brings us closer to a future in which patients have that option. It also provides new clues about the causes and possible treatments of an ailment suffered by tens of millions of people around the world, for which there is no cure and for which there are no clear causes.

A team led by neurologist Juan Fortea, from the Sant Pau Hospital in Barcelona, has analyzed brain samples from more than 3,000 deceased people and brain scans and other diagnostic tests from another 10,000 patients to analyze the effect of carrying two copies of the apolipoprotein 4 gene, or APOE4, in the genome. It was known that this gene carries the highest genetic risk of suffering Alzheimer’s, but until now, it was not clear by just how much.

The study has identified 500 patients who carry this variant and has shown that 95% have early biological markers related to Alzheimer’s, such as the build up of amyloid protein in the brain, which is related to the disease. The study also indicates that the age at which these people will begin to suffer symptoms can be reliably predicted: approximately 65 years, about 10 years earlier than those who carry the other less dangerous APOE gene variants: 3 or 2.

The researchers propose a different way of understanding the disease. According to the study, APOE4 should not only be considered a risk factor for Alzheimer’s, as is the case now, but rather the double copy of APOE4 should be understood as a distinct genetic form of Alzheimer’s. This variant of the disease would be added to the two known types of genetic Alzheimer’s: early Alzheimer’s, caused by very rare mutations, which has been studied for decades in families from Antioquia, Colombia, and Alzheimer’s associated with Down syndrome — nine out of 10 patients ends up developing dementia.

This new form of genetic Alzheimer’s would be by far the most common. “Between 2% and 3% of the entire Caucasian population carries a double copy of the APOE4 gene, which represents millions of people around the world,” explains Fortea in a telephone interview. “In addition, this variant accounts for 15% of all Alzheimer’s cases. Normally we say that the causes of this disease are not known, but with this study we can say that we can explain those 15% of cases,” he adds.

The study, published in Nature Medicine, focused on biological markers associated with the disease, such as amyloid or tau, another harmful protein that builds up in the brain. The next step, Fortea explains, will be to gather data from thousands of patients to determine what risk people with this variant have of being diagnosed with Alzheimer’s, a project that is already underway. If the results corroborate that it is a genetic disease that nearly 100% of people with the variant are predisposed to suffering, current medical guidelines on diagnosis and treatment may change, including the use of genetic tests and the communication of the results to patients.

“I may have dozens of patients affected by this variant, but I should not tell them because clinical practice does not recommend it,” says the doctor. In part, it is because until lecanemab and donanemab, there was no drug capable of modifying the course of the disease.

These two new drugs are the first in decades to provide some benefit against this disease, although their effects are so modest that many patients do not perceive improvement. The first biological markers emerge about 20 years before the onset of symptoms, and once memory loss begins, its progression is unstoppable, which is why it has been so difficult to develop effective treatments. The hope is that these two drugs or others like them can help in earlier stages. Several clinical trials are studying this possibility in patients who have not yet been diagnosed.

The work, says Fortea, also raises a future debate about whether or not patients should take a genetic test to find out if they carry the double APOE4. “There is no good or bad decision. It all depends on how you manage the anxiety of knowing that you have, for example, an 80% chance of suffering from Alzheimer’s. The other day, I was talking to a colleague who said he would never do it; I think I will,” says Fortea.

Pascual Sánchez-Juan, scientific director of the Spanish neurological foundation CIEN, says the study is important because “it helps put this group of people in the spotlight.” He continues: “We have known for 30 years that APOE4 increases the risk of Alzheimer’s, but we put all patients together in the same group if they had one or two copies of the gene, which means that we were not perceiving the differences.”

In Europe, APOE4 has been found to be more common in northern countries than in Mediterranean countries. One of the next steps will be to study more diverse populations, as the current data come almost exclusively from white people in the West. It is possible that the neurological effects of this variant are milder in populations from other regions, particularly Africa, where there appears to be protection from the effects of this variant.

Although the causes of Alzheimer’s disease are unclear, the two main suspects are two harmful proteins, amyloid beta and tau. This study provides important data to improve the understanding of the effect of these two molecules and the treatments against them.

“In the current study,” notes neurologist David Pérez, professor of medicine at the Complutense University of Madrid, not all people with two copies of the APOE4 gene “develop dementia or clinical Alzheimer’s disease, although almost all accumulate brain amyloid at an early age. This early accumulation of amyloid was associated with a much higher risk of developing clinical symptoms and suggests a more direct connection of APOE4 with the pathological mechanisms of the disease, although clarity is still lacking in this regard.”

“An interesting point,” he continues, “is that clinical trials with anti-amyloid antibodies that have demonstrated efficacy, such as lecanemab and donanemab, show that in APOE4 patients the risk of adverse effects is considerably much higher. This has led to reservations among many neurologists about their use in this group. In addition, analysis of efficacy in subgroups of APOE4 homozygotes [with two copies of this gene] has not shown greater effectiveness, and the results are still inconclusive as to whether these therapies are really effective in this specific subgroup. All this leads us to a great paradox; APOE4 homozygotes have an almost universal risk of accumulating brain amyloid after the age of 65 and developing earlier and more aggressive forms of Alzheimer’s, but anti-amyloid therapies do not seem to be more effective in this group and, moreover, are clearly more risky.”

Carlos Dotti, a researcher at the Severo Ochoa Molecular Biology Center in Madrid, believes that these observations “reinforce the concept that this disease, except in certain very specific cases, can be initiated by defects occurring outside the brain. It has long been suggested that cardiovascular and metabolic deficits play a significant role in its development, such as hypertension, Type 2 diabetes, arrhythmias. This work serves to confirm that a specific metabolic and cardiovascular condition, such as what occurs when one inherits both APOE4 alleles, is a definitive cause of disease, not simply a risk factor.”

Francesc Guix, a bioengineering specialist at the Ramón Llull University in Spain, explains further. “The primary defect of being a carrier of the two E4 alleles is elevated levels of total cholesterol, LDL cholesterol and triglycerides, and decreased levels of HDL cholesterol. Any clinician knows that these alterations will lead to cardiovascular problems, which, among other consequences, will affect cerebral oxygen flow. In addition, vascular alterations lead to an increase in inflammatory processes that will damage the brain. On the other hand, the two APOE4 alleles can also contribute to the development of Alzheimer’s due to the actions that this protein plays at the level of the brain, both in relation to cholesterol transport between the different cell populations in the aggregation of the beta-amyloid peptide and its elimination from the brain,” he concludes.

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