A single gene mutation protects against Alzheimer’s disease in people who are destined to get the disease very young – and now we know why.
The gene mutation affects a protein called reelin that directs brain cells to tear down the likely culprits of the disease – toxic amyloid plaques and tau tangles. The mutation makes reelin work much more efficiently, new research shows.
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A tale of two genes
Unraveling how the protective mutation worked began with a population facing the opposite problem: an exceptionally deleterious mutation that accelerates Alzheimer’s disease.
For decades, people in the lush valleys near Medellin, Colombia, had faced premature memory loss.
Neurologist Dr. Francisco Lopera grew up in the region. While still a medical student, he came across his first case, a 47-year-old man who showed memory symptoms typically seen in older people with dementia. Lopera traveled across the region, determined to map where people faced early memory loss. He eventually identified thousands of people affected by a rare genetic form of Alzheimer’s disease. The condition was autosomal dominant, meaning that anyone carrying at least one copy of the mutated presenilin 1 (PSEN1)) the gene would, like clockwork, lose its memories in its mid-forties.
Lopera’s work mapping this affected population was invaluable to dementia research, but his most important contribution came just one year before his death in 2024. He co-authored an article in the journal Natural medicine who described the case of a patient he met on his travels across Colombia. This patient had the PSEN1 gene mutation but lived well into his 60s before developing Alzheimer’s. This was the neurological equivalent of a house standing for decades despite cracks in the foundation that should give way.
Lopera discovered that this man’s resilient brain was enhanced by another mutation, called COLBOS after the research centers in Colombia and Boston that characterized it.
Improving efficiency
The new researchpublished in December 2025 in the Journal of the American Chemical Society, has identified exactly how the COLBOS mutation protected the patient’s brain for decades.
When the COLBOS variant was first identified in 2023, researchers noted that the mutation changed how a cell signaling protein called reelin worked. The protein promotes the formation of new connections between brain cells, prevents the toxic tau protein from being activated, and prevents amyloid plaques from building up in the brain.
COLBOS changed how reelin binds to another signaling molecule called heparan sulfate, a sugar found on the cell surface of virtually all human cell types, including neurons. But how reelin’s binding ability affected Alzheimer’s progression remained unclear. In the new article, molecular biologist Chunyu Wang and colleagues at Rensselaer Polytechnic Institute in New York mapped this process.
Wang’s study relied on a technique called surface plasmon resonance, which reveals how strongly a free-floating molecule – in this case reelin – binds to a molecule anchored to a sensor surface – in this case heparan sulfate. Wang’s team saw that the COLBOS mutation acted as a molecular glue, strengthening the bonds between the two molecules, suggesting that it may cause reelin to accumulate on the surface of neurons in the brain.
This change explained why COLBOS was able to stave off Alzheimer’s. When reelin binds to heparan sulfate, the protein is localized to the surface of brain cells, where its anti-Alzheimer’s signaling is most effective. Here, reelin can more easily stave off cognitive decline by slowing important Alzheimer’s disease processes, such as phosphorylation of the tau protein, Wang said. Phosphorylation destabilizes the normally ordered structure of tau, causing toxic tangles to build up in neurons.
Herz mapped much of the coil way 20 years ago in a series of newspapers. Herz’s work was in mice, and although his team predicted reelin mutations could be neuroprotective, it was only through Lopera’s tireless clinical work that the theory was proven.
Uphill battle
Unfortunately, as Lopera noted, the COLBOS mutation could only delay rather than prevent people with rare Alzheimer’s mutations from getting the disease. Herz’s theory is that patients with PSEN1 mutations show malfunctions in organelles called endolysosomal compartments. These are like cellular shredders that cut up troublesome proteins such as tau and amyloid. He added that the COLBOS mutation makes the process of feeding these proteins into the shredder more efficient.
But as the brain ages, Herz said, the shredding defects become harder to overcome, despite reelin’s effects, leading to Alzheimer’s.
The findings may have useful implications for future Alzheimer’s therapies that delay or prevent disease in the vast majority of patients, including those without high-risk PSEN1 mutations. Wang pointed to recent research that showed reelin-producing neurons are some of the first to die in Alzheimer’s disease. Without these neurons, less reelin is made, toxic waste builds up and Alzheimer’s disease accelerates.
Wang hypothesized that if they could make reelin act more effectively on brain cell surfaces, even with less reelin present, it could protect such people from further symptoms. Wang is currently discussing with a colleague at Rensselaer the development of a gene therapy that enhances reelin signaling based on these findings.
Wang pointed out that even if researchers could delay Alzheimer’s by a fraction of the two decades that the COLBOS mutation gave the Colombian patients, it would be by far the largest disease improvement ever realized with Alzheimer’s. Current medications on the market for the condition can extend independent life with two to three years tops, he said, so “20 years is amazing.”
