A new study in Nature Neuroscience is drawing attention to a subtle DNA pattern that may influence a person’s odds of developing Alzheimer’s disease. Rather than focusing on a single genetic mutation, researchers looked at repeated stretches of DNA and how they might affect Alzheimer’s risk. Their work, centered on a gene called FAM193B, suggests that a simple three-letter DNA sequence repeated multiple times could be linked to higher susceptibility, especially among people of Chinese ancestry. This kind of finding may help refine Alzheimer’s disease risk prediction over time, even though it is not yet ready to guide treatment or prevention.

Alzheimer’s disease has long been understood as a complex condition influenced by genetics, lifestyle, and environment. Having a parent or sibling with the disease can increase a person’s chances of developing it, yet there is no guarantee that family history will lead to Alzheimer’s. Researchers have identified several genetic variants connected to risk, including the well-known APOE gene and its APOE4 variant, which is considered the strongest established genetic risk factor so far. Still, common genetic variants captured in earlier large studies explain less than half of the disease’s heritability. That gap has led scientists to search for other types of genetic changes, such as structural variations and repeated DNA sequences, that might account for some of the missing risk.

In this new work, experts based at institutions in Hong Kong turned their attention to a pattern known as a CCG repeat. These three DNA letters appear in a region that regulates the gene FAM193B. Instead of asking whether a particular spelling change raises risk, the researchers asked whether having more copies of this three-letter unit might matter. This approach goes beyond the familiar “single-base” changes often tested in genome-wide association studies and opens the door to a broader view of genetic architecture in Alzheimer’s.

The research team examined a Chinese cohort of more than 3,000 people, roughly half with Alzheimer’s disease and half serving as controls. They also drew on genetic data from the UK Biobank, which included around 2,600 individuals with Alzheimer’s and nearly 23,000 without it, to see whether any patterns they observed would extend to people of European ancestry. From a subset of 11 Chinese participants, they constructed a detailed reference of structural DNA arrangements, then used that guide to interpret the DNA data for everyone else in the study.

Across the participants, the CCG sequence varied in length. Some people had as few as four repeats, while others carried up to 30. When the researchers looked at who had Alzheimer’s disease, a pattern emerged. Individuals with at least 18 CCG repeats had about twice the odds of having Alzheimer’s compared with those who carried no more than 11 repeats. Importantly, this association described an increased likelihood of having the disease in the studied group, not a guaranteed outcome for any one person and not an exact measure of lifetime risk for the broader population.

The investigators then turned to the UK Biobank data to see whether people of European ancestry showed a similar link between CCG repeats and Alzheimer’s. They did find an association, although it was notably weaker than in the Chinese cohort. This difference in effect size across ancestries is not unexpected. Experts pointed out that many genetic variants, including APOE, influence risk to varying degrees depending on ancestral background. The message for now is that the FAM193B CCG repeat appears to be relevant in more than one population, but its impact is not uniform worldwide.

To explore what might lie behind the association, the researchers studied how CCG repeat length affects FAM193B activity. They found that longer CCG tracts led to higher expression of the FAM193B gene. When FAM193B expression was elevated in neuronal cells, it was associated with DNA damage and cellular harm. Analyses of postmortem human brains and cultured neurons suggested that increased FAM193B activity connects with pathways involving DNA damage and cell death. These are central themes in Alzheimer’s disease biology, which often features cumulative harm to nerve cells over time.

The study also reported that FAM193B protein directly interacts with two enzymes, GSK3alpha and GSK3beta. These enzymes are already of interest in Alzheimer’s research, because their dysregulation has been linked to increased levels of beta-amyloid and tau. Beta-amyloid and tau are the hallmark proteins that accumulate in plaques and tangles in the brains of people with Alzheimer’s. The possibility that FAM193B might influence these enzymes gives researchers a potential mechanistic bridge between a DNA repeat, gene expression, and the classic protein changes seen in the disease. Some experts have suggested that this line of evidence makes FAM193B an especially intriguing target for further functional studies, including research into how it might affect tau pathology downstream of amyloid deposition.

Despite these compelling connections, scientists emphasize that the story is far from complete. The biological function of FAM193B is still not fully defined, and the presence of longer CCG repeats does not automatically mean that neurons will be damaged or that an individual will develop Alzheimer’s. The authors and outside commentators have been careful to note that this genetic feature explains part of the risk picture and that additional factors, both genetic and non-genetic, remain critically important.

Looking ahead, the most immediate implication of this work appears to be in the realm of Alzheimer’s disease risk prediction. Incorporating structural variants like the FAM193B CCG repeat into risk models, with appropriate adjustments for ancestral background, may help clinicians refine estimates of a person’s likelihood of developing the disease. However, experts also caution that it is too early to draw firm conclusions about prevention or treatment based on these findings alone. Larger studies in diverse populations will be needed to confirm the strength and consistency of the association. At the same time, more laboratory research is required to understand the biochemical and physiological consequences of altering FAM193B expression.

Several researchers who commented on the study described it as exciting and potentially important, particularly because it highlights both the value of structural variants and the necessity of studying diverse populations. By expanding genetic analyses beyond single-letter variants and beyond a narrow set of ancestries, this work may help fill in some of the missing pieces in Alzheimer’s heritability. While the discovery does not yet change how patients are treated, it offers a clearer glimpse into the biological pathways that could one day be targeted for therapy. For now, the FAM193B CCG repeat stands as a promising lead that deepens our understanding of how subtle patterns in DNA can shift the odds of a complex disease like Alzheimer’s.

Read more at https://www.newsweek.com/pattern-linked-to-higher-alzheimers-odds-study-12592065