Alzheimer's disease risk-increasing genes could be an inherited variant of the condition, according to scientific findings.

Researchers suggest that certain genes linked to an increased risk of Alzheimer's could actually be inherited types of the disease.

Investigators involved in a recent study, published in the journal Nature Medicine, suggest that around 1 out of every 6 cases of Alzheimer's disease could be considered inherited or familial. This adjustment in perspective is attributed to an improved comprehension of the role played by the fourth gene known as apolipoprotein E (APOE), which is responsible for creating a protein that carries lipids in the body and brain. APOE contributes to the deposition or removal of sticky beta amyloid plaques, a hallmark of Alzheimer's disease.

Alzheimer's disease is categorized into two types: familial and sporadic. The majority of cases are believed to be sporadic, manifesting later in life. In contrast, familial forms are attributed to mutations in three genes and are known to be quite uncommon, accounting for around 2% of all Alzheimer's diagnoses or approximately 1 in 50 cases.

Based on the new understanding, almost double the number (1 in 6 cases) of Alzheimer's would be categorized as inherited.

The increasing recognition of the role of the APOE gene in Alzheimer's disease is partly because of its potential to enhance the risk of developing this ailment when a person carries two copies of it. A particular variant of this gene, known as APOE4, is detrimental and has long been associated with a heightened risk of Alzheimer's disease. Those with one copy of APOE4 have a slightly increased risk, whereas individuals having two copies display a much higher risk.

Now, researchers propose that APOE4 should no longer be perceived as just a risk factor; instead, it should be regarded as an inherited form of the disease, almost ensuring that people with two copies will exhibit signs of Alzheimer's in their brain.

Examining the APOE gene's role in Alzheimer's disease

Scientists from Spain and the United States explored this aspect further by contrasting individuals in clinical trials with two copies of the APOE4 gene to those with other forms of the APOE gene. Additionally, they investigated persons carrying two copies of APOE4 compared to those with other inherited forms of the disease, specifically early-onset autosomal dominant Alzheimer's disease (ADAD) and Down syndrome-associated Alzheimer's disease (DSAD). This analysis incorporated data from around 3,300 brains stored at the National Alzheimer's Coordinating Center and data from over 10,000 individuals enrolled in five separate clinical trials.

The results were significant. People with two copies of the APOE4 gene had a substantially higher likelihood of developing the biological changes associated with Alzheimer's disease, sharing similarities with those who had other inherited versions of the disease. Moreover, nearly 95% of people with two copies of APOE4 developed Alzheimer's symptoms by the age of 82.

Although the presence of APOE4 guarantees the development of the biological changes linked to Alzheimer's, it does not necessarily lead to cognitive decline. There have been rare instances where individuals with APOE4 have displayed a significant amount of beta amyloid in their brain but have not developed symptoms, potentially due to protective genetics or environmental factors. In a sizable collection of approximately 3,300 brains studied by the National Alzheimer's Coordinating Center, 273 people had two copies of APOE4, and 240, or 88%, exhibited signs of dementia.

It is also noteworthy that people with two copies of APOE4 tend to show symptoms of Alzheimer's disease earlier in life and experience a more severe form of the disease. Significantly, the progression and manifestation of the disease in both inherited and non-inherited forms of Alzheimer's show remarkable similarities.

As a consequence of these findings, the team behind the study believes having two copies of the APOE4 gene should be regarded as a genetic form of the disease, rather than simply a risk factor.

Dr. Charles Bernick, the associate medical director at the Cleveland Clinic Lou Ruvo Center for Brain Health, applauded the study, stating that it solidified the idea that possessing two copies of APOE4 is highly influential in the development of Alzheimer's disease.

Validation of the idea that having two copies of the APOE4 gene can drive the disease process adds weight to the need for further research in understanding and potentially treating this form of the disease.

The influence of APOE4 in the growth of Alzheimer's wasn't acknowledged earlier, scientists believe, as APOE4 also holds a pivotal position in heart health matters. They surmise that a large number of individuals with two copies of the gene might have perished from cardiovascular complications prior to developing Alzheimer's.

The scientists also noticed a gene-dose effect. Carrying two copies of APOE4 affirms that a person will experience accumulation of beta amyloid and tau in their brain, whereas possessing just one copy of the gene enhances the probability of the person having a higher risk but not like having two copies of the gene.

APOE4 being passed down as an inherited ailment carries significant implications. It suggests that genetic factors are more central in the prevalence of Alzheimer's than was formerly grasped.

Earlier to APOE4, no other genetic modifications were identified to cause Alzheimer's, except in cases related to early-onset forms of the disease and Down's syndrome. Together, these represented under 2% of Alzheimer's instances - roughly 1 in 50.

People with two copies of the APOE4 gene account for nearly 15% of those identified with Alzheimer's, or approximately 1 in 7 cases of the disorder.

Around 2% of the general population is accompanied by two copies of the APOE4 gene, making it one of the most widespread hereditary diseases.

Tests for identifying APOE4 are not widely recommended

It's also likely to influence how those bearing the APOE4 gene are identified and treated.

Tests exist to determine an individual's APOE4 status, but they're not advocated as part of the standard diagnostic procedure. This perspective may need to alter.

"The consensus and the guidelines don't advocate testing for APOE4, and that was due to the consensus that it didn't aid in the diagnosis," Fortea explained.

APOE4 testing is advised for individuals being examined for taking fresh amyloid-removing medications, such as lecanemab.

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Alzheimer's patients carrying two copies of the APOE4 gene face a higher risk for serious side effects like brain swelling from new amyloid-removing medicine, prompting certain treatment centers to decline offering the medication.

"I find this highly disconcerting given these data," explained study coauthor Dr. Reisa Sperling, director of the center for Alzheimer's Research and Treatment at Brigham and Women's Hospital.

She emphasized the necessity of conducting research to ascertain whether it might be feasible to identify safer dosages or safer treatments for this group of patients.

"For me, this simply means we need to initiate treatment earlier," Sperling remarked, "and this research truly indicates that we should be treating them much sooner, at a younger age, and at an early stage of pathology, as we know they are most likely to experience rapid deterioration."

Dr. Sterling Johnson, who heads the Wisconsin Registry for Alzheimer's Prevention at the University of Wisconsin, underscored the importance of considering APOE4 status during clinical trials.

"It's crucial for clinical trials to account for participants' APOE4 status in the future," Johnson said, who is also a coauthor in the news conference and highlighted, "so that we can genuinely understand the relationship between amyloid accumulation and tau and symptoms in people with two copies of the APOE4 gene, which we really haven't been able to do before."