An Alzheimer’s mutation may delay disease onset by about 20 years in people otherwise expected to develop memory loss in their mid-40s.
The mutation affects a protein called reelin, which directs brain cells to break down amyloid plaques and tau tangles, harmful protein build-ups linked to Alzheimer’s.
New research suggests the mutation makes reelin work much more efficiently.
The discovery follows decades of work in the valleys near Medellin, Colombia, where thousands of people carry a rare inherited form of Alzheimer’s caused by a mutation in the presenilin 1, or PSEN1, gene.
Anyone carrying even one copy of the altered gene would be expected to lose their memory in their mid-40s.
The late neurologist Francisco Lopera, who grew up in the region, spent years mapping the affected population.
A year before his death in 2024, he co-authored a paper on a patient who carried the PSEN1 mutation but lived well into his 60s before developing Alzheimer’s.
Lopera found that the man’s brain was protected by another mutation, dubbed COLBOS after the research centres in Colombia and Boston that characterised it.
Research published in December 2025 by molecular biologist Chunyu Wang and colleagues at Rensselaer Polytechnic Institute in New York has now shown how COLBOS works.
The mutation alters how reelin binds to a sugar molecule called heparan sulfate on the surface of brain cells, strengthening that bond and helping reelin build up where its protective signalling is most effective.
There, reelin can help slow key disease processes, including phosphorylation of tau, a chemical change that destabilises the protein and causes toxic tangles to build up in neurons, the brain’s nerve cells.
Joachim Herz, a neuroscientist at the University of Texas Southwestern Medical Center who was not involved in the research, 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.
“That I would never have in my wildest dreams predicted.”
Herz, who mapped much of the reelin pathway 20 years ago in mice, believes the COLBOS mutation may make the process of feeding harmful proteins into cell structures that break them down more effective.
However, as the brain ages, defects in those structures may become harder to overcome despite reelin’s effects, meaning the mutation may delay Alzheimer’s rather than prevent it.
The findings could still have implications for future therapies for the far larger number of patients who do not carry high-risk PSEN1 mutations.
Wang pointed to recent research showing that reelin-producing neurons are among the first to die in Alzheimer’s, and suggested that making reelin work more efficiently at brain cell surfaces, even when less of it is present, could protect people from further symptoms.
He is now discussing the development of a gene therapy to enhance reelin signalling based on the findings.
Wang said that even delaying Alzheimer’s by a fraction of the two decades linked to the COLBOS mutation would be a major advance.
Current drugs on the market may extend independent living by two to three years at most, he said, so “20 years is amazing.”
