Can a person carry a major genetic risk for dementia and still keep their memory into old age? A small number of people appear to have done exactly that. Studying them is giving researchers some of the most promising clues yet about how Alzheimer’s disease might be stopped.
Two kinds of genetic risk
Genes influence Alzheimer’s in very different ways. At one extreme are rare mutations that all but guarantee the disease. One of them, known as the “Paisa” mutation, sits in a gene called presenilin 1 (PSEN1). People who carry it typically develop memory and thinking problems around their mid-40s. A huge extended family in Colombia has been followed by scientists for roughly four decades. It includes about 6,000 blood relatives, of whom about 1,200 carry the Paisa variant. expressandstarexpressandstar
At the other extreme is APOE4, the strongest common genetic risk factor for late-onset Alzheimer’s. Roughly a quarter of people of European ancestry carry it. One copy is estimated to raise risk two- to threefold, and two copies about tenfold. Risk is not destiny, though. Many APOE4 carriers never develop the disease, and scientists have long wanted to know why. progress
The woman who waited
In 2019, researchers described a puzzling case. A woman in that Colombian family had the PSEN1 mutation, yet whole exome sequencing found she also carried two copies of a rare APOE3 variant called Christchurch. The variant is named for the New Zealand city where it was first identified. She stayed free of dementia until her late 70s, decades after relatives with the same mutation typically fall ill. newswiseexpressandstar
Her brain scans were revealing. Her brain held significant amyloid plaques, and yet it maintained normal glucose metabolism in regions usually hit by the disease. The leading interpretation is that Christchurch did not stop amyloid from building up. Instead, it may have kept tau protein, whose tangles are linked to Alzheimer’s, from collecting in her brain. That distinction matters, because tau pathology tracks closely with cognitive decline. psychiatristNewsweek
A single patient proves little, and the authors said so. The question was whether the effect would hold up in others.
A larger test
In 2024, a team led by Francisco Lopera at the University of Antioquia in Colombia reported findings in the New England Journal of Medicine. Twenty-seven relatives who carried the Paisa mutation plus one copy of Christchurch also had delayed symptoms, with impairment starting around age 52. That is about four years later than in carriers without the variant. expressandstar
The effect was weaker than in the woman with two copies, but a four-year delay in a condition this severe is still significant. It also hints at a dose effect, where more protective variant means more protection. Dr. Joseph Arboleda-Velasquez of Mass Eye and Ear said the work raises confidence that the target is not only protective but “druggable.” expressandstar
Not an isolated case
Christchurch is not the only protective variant. In 2022, a Stanford-led collaboration published a study in JAMA Neurology. It analysed the genomes of more than 500,000 people with and without Alzheimer’s. The team found a variant called R251G, which alters a single amino acid in the APOE protein. It is found in fewer than 1 in 1,000 people and is always inherited alongside APOE4, so those who carry it also carry the high-risk gene. The researchers also reported a second protective mutation, V236E, which sits alongside APOE3 and lowered Alzheimer’s risk by about 60%, similar to the protective APOE2 variant. rare mutation negates alzheimers risk posed by apoe gene variant +3
Several different mutations in the same gene all point the same way: tweaks to APOE can blunt a dangerous genetic hand.
Could this lead to treatment?
That is the hope, though it is early. Researchers describe a shift in strategy. As study author Yakeel Quiroz put it, the case opens a door to treatments based on resistance to Alzheimer’s pathology rather than on its cause. Instead of only trying to clear plaques, drug developers could try to imitate what these protective variants do. alzinfo
Dr. Yann Le Guen, co-lead author of the Stanford study, said the finding could help develop drugs that mimic the protective variant’s effect. Quiroz said her team is now studying brain resilience in relatives with one copy of Christchurch, using MRI scans, cognitive testing and blood biomarkers. progressexpressandstar
What this does not mean
Several cautions apply. The protective variants are very rare, so most people will never carry one. The best-studied evidence comes from one unusual family with a specific, near-deterministic mutation, and it may not translate neatly to the far more common late-onset disease. No therapy based on these discoveries has been proven, and there is no test result or lifestyle change that gives a person this protection. A delay of four years, or even a few decades in one extraordinary case, is also different from a cure.
The bigger picture
For anyone who worries about dementia, these stories carry a quiet message. Genes shape risk, but they do not always decide the outcome, and the people who escape the expected fate may point the way for everyone else. The woman in Colombia and her relatives have given science an unusually clear window into how the brain can resist a disease that devastates millions. Turning that window into a treatment will take years of work, but for the first time researchers have a specific biological target to aim at.
