A single gene mutation protects against Alzheimer's disease in people 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 shred the probable culprits in the disease — toxic amyloid plaques and tau tangles. The mutation makes reelin work much more efficiently, new research reveals.
The finding could point the way towards transformative therapies for the condition, experts said.
"I would never have expected that it would be so protective that it actually negates the effect of a dominant early onset Alzheimer's disease mutation," Dr. Joachim Herz, a neuroscientist at the University of Texas Southwestern Medical Center who was not involved in the new research, told Live Science. "That I would never have in my wildest dreams predicted."
A tale of two genes
Unpacking how the protective mutation worked began with a population that faced the opposite problem: an extraordinarily harmful 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 he was still a medical student, he came across his first case, a 47-year-old man displaying memory symptoms usually seen in elderly people with dementia. Lopera traveled across the region, determined to map where people were facing early memory loss. He ultimately 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) gene would, like clockwork, lose their memories in their mid-forties.
Lopera's work in mapping this affected population was invaluable to dementia research, but his most important contribution came just a year before he died in 2024. He co-authored a paper in the journal Nature Medicine that detailed the case of a patient he met in 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 that stays standing for decades despite cracks in its foundations that should give way.
Lopera discovered that this man's resilient brain was strengthened by another mutation, dubbed COLBOS after the research centers in Colombia and Boston that characterized it.
Improving efficiency
The new research, published 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, scientists noted that the mutation altered how a cell signaling protein called reelin functioned. The protein promotes the formation of new connections between brain cells, prevents the toxic tau protein from becoming activated, and prevents amyloid plaques from building up in the brain.
COLBOS altered how reelin binds to another signaling molecule called heparan sulfate, a sugar found on the cell surface of virtually all cell types in humans, including neurons. But how reelin's binding ability affected Alzheimer's progression remained unclear. In the new paper, molecular biologist Chunyu Wang and colleagues at the Rensselaer Polytechnic Institute in New York mapped this process.
Unfortunately, as Lopera noted, the COLBOS mutation could only delay rather than prevent people with rare Alzheimer's mutations from getting the disease.
Wang is currently discussing with a colleague at Rensselaer the development of a gene therapy that enhances reelin signaling based on these findings.
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