Groundbreaking new discovery predicts early onset of Alzheimer’s disease

The slow loss of memory, thinking, and independence that defines Alzheimer’s disease continues to affect millions worldwide. One rare but revealing form of the condition, known as familial Alzheimer’s disease, is offering scientists new insight into how and when the disease begins.

This inherited form of the disease tends to strike early—often before the age of 65—and is caused by mutations in just three genes. These mutations act like molecular clocks, offering clues not only about the cause but also about the timing of the disease.

Most cases of Alzheimer’s disease are sporadic and develop later in life. However, less than 1% of cases result from inherited mutations in three specific genes: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), and Amyloid Precursor Protein (APP). These mutations drive the early-onset form of the disease, also known as autosomal dominant Alzheimer’s disease (ADAD). Because of its clear genetic basis, this rare form has become a key model for understanding the disease’s origins.

The PSEN1 and PSEN2 genes encode similar proteins that act as core parts of a complex enzyme system called γ-secretase. This system cuts the APP protein into smaller fragments called amyloid-beta (Aβ) peptides. These fragments—especially the longer ones—can clump together in the brain to form amyloid plaques, one of the telltale signs of Alzheimer’s.

A research team led by Prof. Lucía Chávez Gutiérrez at the VIB-KU Leuven Center for Brain & Disease Research has recently mapped how specific mutations in these three genes affect the production of Aβ peptides.

Their work, published in Molecular Neurodegeneration, offers a better understanding of how changes in Aβ peptide profiles correlate with the age at which symptoms begin. “We have developed a method to experimentally test how likely a mutation is to cause the disease, as well as to predict disease onset,” explains Chávez Gutiérrez.

Under normal conditions, the γ-secretase enzyme cuts APP into both short and long Aβ fragments. When this process works correctly, it limits the buildup of harmful plaques. But mutations in PSEN1, PSEN2, or APP shift this balance, leading to the release of longer, stickier Aβ42 and Aβ43 peptides. These forms are more likely to clump and start the harmful chain of events that eventually kill brain cells.

One of the group’s key findings is that the proportion between short and long Aβ peptides is a strong predictor of when Alzheimer’s symptoms begin. “Our data predicts that a 12% shift in Aβ profile could delay the age of onset in familial Alzheimer’s disease by up to 5 years,” Chávez Gutiérrez says. The research highlights how early changes at the molecular level can act as a countdown clock toward disease.

This relationship is especially clear in individuals with PSEN1 mutations. The team found that the earlier symptoms began, the more severely the mutations had shifted the Aβ ratio toward longer peptides. The results also extended to mutations in PSEN2 and the APP gene, though with more variation. Even within the same family, people carrying the same PSEN2 mutation showed very different ages of onset.

To make sense of this variability, the researchers analyzed more than 160 different PSEN1 mutations. They found a strong linear correlation between Aβ profiles produced in lab settings and the age at which symptoms began in patients. A specific formula—based on the ratio of short to long peptides—served as a reliable predictor of symptom onset.

Sara Gutiérrez Fernández, first author of the study, explained, “When we put all of our data together, it gives us a much clearer picture of how each of the causal genes contribute to the development of familial Alzheimer’s disease—we can measure the exact contribution of each gene and even predict when the first symptoms will appear.”

By applying the same formula to PSEN2 and APP mutations, the researchers developed a broader framework. This tool can now be used to assess how pathogenic a particular genetic variant is and estimate when symptoms are likely to develop. This is a major step forward for doctors working with patients who carry familial Alzheimer’s genes.

Although some clinical trials targeting Aβ have failed, recent anti-amyloid immunotherapies are showing new promise. The U.S. Food and Drug Administration has approved a few drugs that slow the disease’s progression by clearing Aβ from the brain. These treatments work best in the earliest stages, before too much damage is done.

Knowing when symptoms are likely to start could help doctors apply these treatments more effectively. If a shift in the Aβ profile can delay symptom onset by years, then treatments designed to reverse or prevent that shift could offer real hope.

Chávez Gutiérrez and her team believe that drugs which encourage the production of shorter, less harmful Aβ peptides could delay or prevent disease onset altogether. “This highlights the potential of therapies that target γ-secretase in the brain to create shorter forms of Aβ,” she notes.

Beyond improving diagnosis and prediction, the research also points to more personalized care for patients. Some people with these mutations don’t get sick until much later in life, possibly because of protective genetic factors or healthier environments. By comparing their data with expected Aβ profiles, researchers may be able to identify these protective modifiers in future studies.

This framework, then, does more than model disease—it opens the door to precision treatment plans. “We have developed a predictive model for age of onset that could pave the way for personalized approaches to managing familial Alzheimer’s,” says Gutiérrez Fernández. “In the future, this may help clinicians to more effectively design strategies for early diagnosis and treatment for patients with genetic forms of the disease.”

What started as a close look at three genes and their role in Aβ production has become a much larger toolset. These findings could help reshape how doctors and scientists think about Alzheimer’s disease—especially when it runs in families. And as therapies continue to evolve, so does the hope that one day the clock won’t have to run out for those at risk.

Note: The article above provided above by The Brighter Side of News.

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