Researchers identified three gene variants linked to the timing and progression of inherited Alzheimer’s. 

The study, published in The Lancet Neurology, focused on autosomal dominant Alzheimer’s disease (ADAD), a rare inherited form of Alzheimer’s caused by mutations in one of three genes: APP, PSEN1 or PSEN2.  

Although the condition accounts for only about 1 percent of Alzheimer’s cases, people who inherit these mutations are highly likely to develop the disease, often at a relatively young age. 

One long-standing mystery has been why Alzheimer’s symptoms can begin at different ages, even among people carrying the same disease-causing mutation.  

To investigate, researchers analyzed whole-genome sequencing data from 101 people with symptomatic ADAD and compared their genetic profiles with more than 5,000 individuals without a known ADAD mutation. The team discovered significant associations involving three genetic regions linked to the genes CNIH4, CCNG1, and RHOJ.  

Each appeared to modify Alzheimer’s risk or progression independent of the underlying inherited mutation. 

One of the strongest findings involved a variant in CCNG1, which was associated with an earlier age of dementia onset. Carriers of the risk allele developed dementia roughly a decade earlier than those without it.  

The same variant was also linked to higher levels of TDP-43, a protein implicated in several neurodegenerative diseases, and signs of accelerated brain aging on MRI scans. 

The researchers also found that a variant in RHOJ was associated with biological markers of more severe Alzheimer’s disease. Individuals carrying the risk allele had higher levels of total tau and phosphorylated tau 181 in cerebrospinal fluid and a lower Aβ42/Aβ40 ratio—changes commonly associated with Alzheimer’s pathology.  

Meanwhile, a variant within CNIH4 showed one of the strongest associations with Alzheimer’s risk among mutation carriers, suggesting it may play an important role in how the disease develops. 

Senior author Dr. Cyril P. Pottier of the Washington University School of Medicine said identifying genetic modifiers could help explain why disease trajectories differ so widely among people with inherited Alzheimer’s.  

Researchers hope that understanding these pathways may eventually improve genetic counseling, refine clinical trial design, and uncover new therapeutic targets.  

Although the findings were made in people with a rare inherited form of Alzheimer’s disease, the researchers also examined whether the variants were associated with age at onset in thousands of people with sporadic Alzheimer’s disease, the far more common form of the condition. 

The results add to a growing body of evidence that genes beyond the well-known Alzheimer’s risk factors can influence how the disease unfolds.  

By revealing biological pathways that can either accelerate or potentially delay decline, scientists hope to identify new strategies for preventing or slowing Alzheimer’s—not only in families with inherited disease, but in the broader population as well.  

Reference

Patel M, Feng W, Mckay N et al. Identification of genetic modifiers of autosomal dominant Alzheimer’s disease: a genome-wide association study. The Lancet Neurology, 25, 581-590.

Contact Newsweek editors on this story: Kara Dolman and Sam Wilson.

Related Articles

Start your unlimited Newsweek trial