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HomeCase ReportPatients who defied Alzheimer's gene may help with therapies

Patients who defied Alzheimer's gene may help with therapies

Scientists believe there may be a "pathway for prevention and cure" after a Columbian man, who died in 2019, became only the second patient identified with the remarkable ability to defy the Alzheimer’s gene, providing hope for future therapies and treatments.

The man, who was first evaluated by neurologists at 67, was cognitively normal, and neither he nor his family had concerns about his memory. So scientists began to follow his extraordinary case closely. The father of two had been born with a particularly sinister gene mutation that should have doomed him to dementia before his 50th birthday, reports The Washington Post.

Instead, his life had been one of remarkable resilience, bucking the script written in his genes. The cognitive impairment that should have started at age 44 stayed at bay for more than two decades. Rather than dying in his early 60s, he retired. He did eventually develop moderate dementia, and died in 2019 at 74.

He is only the second patient identified with the miraculous ability to defy the devastating Alzheimer’s gene, reported an international team of scientists recently in the journal Nature Medicine. Doctors hope the two known cases will allow researchers to develop new treatments to protect other people with Alzheimer’s disease, which affects 6.7m people in the US.

The researchers sifted through the man’s genome to identify a different mutation that may have helped protect him against the disease. They also used brain scans taken when he was 73 to home in on a key region that appears to have been relatively protected against the tau protein tangles that typically occur in Alzheimer’s patients.

“I think it’s important we listen to the patients. And I think what the patients are telling us is … there is a pathway for protection,” said Joseph Arboleda-Velasquez, an associate scientist at Mass Eye and Ear, a Harvard teaching hospital, and one of the study’s leaders.

“These are very provocative findings, and think these cases have something important to teach us about resilience to disease and the biology of Alzheimer’s,” said Gil Rabinovici, a neurologist at the University of California San Francisco, who was not involved in the study.

“This raises a number of interesting questions, and I don’t know that we have the answers.”

A genetic time bomb

For decades, neurologist Francisco Lopera at the University of Antioquia in Medellín, Colombia, has been caring for and following an extended family, many of whom carry a tragically unlucky mutation in a gene called presenilin 1. The mutation is rare, and its effects are aggressive and predictable.

By their late 20s, people who carry the mutation have brains clogged with the hallmark amyloid plaques that characterise Alzheimer’s disease. By their mid-30s, tangles of a different protein associated with Alzheimer’s, tau, appear.

People carrying this gene begin to experience the first inklings of cognitive problems at around 44, and by 49, they have full-blown dementia. They typically die in their 60s.

In total, scientists have discovered 1 200 people out of an extended family of more than 6 000 carrying this genetic time bomb.

Yakeel Quiroz, director of the Familial Dementia Neuroimaging Lab at Massachusetts General Hospital, has worked with Lopera and these patients for 20 years.

“You meet them before they have symptoms, and you see them progress,” Quiroz said. “You get to … see how they become severely demented – and how they die. There’s nothing you can do to stop it.”

But in 2019, researchers discovered a single patient, Aliria Rosa Piedrahita de Villegas, who seemed to have fended off fate.

Her memory didn’t start to decline until she was in her 70s. Scientists discovered a genetic mutation that protected her, nicknamed Christchurch. Although her brain was clogged with the characteristic amyloid plaques of Alzheimer’s, it was relatively free of the tangles of tau also associated with the disease.

Scientists marvelled at the case but also debated its relevance. This was only one person. Was it an aberration, or a path to follow? What could this one person reveal about how to fight Alzheimer’s in the broader population?

The discovery of a second person with genetic resilience validates the quest but also deepens the mystery.

The man, whose identity is anonymous at his family’s request, didn’t have the Christchurch gene variant. He appeared to have been protected due to a mutation in a different gene called reelin.

What’s more, both patients had brains riddled with amyloid plaques, which have so far been a key target in therapies for Alzheimer’s.

Recently, drugs aimed at clearing amyloid plaques have been approved in the US, the first beacons of hope in decades. But these drugs are far from a cure. They aim to slow the progression of the disease, but have fostered debate and criticism over whether modest benefits outweigh their risks and costs.

The controversial approval of an Alzheimer’s drug reignites the battle over the underlying cause of the disease

The woman’s lack of tau tangles supported an alternate avenue for therapeutics. When the man had his brain scanned at 73, researchers found he had both amyloid plaques and tau tangles associated with Alzheimer’s. But crucially, tau was relatively limited in his entorhinal cortex, which is essential for memory.

“The possibility that just by protecting the entorhinal cortex, even if you have a lot of Alzheimer’s pathology elsewhere, you can have that protection… Wouldn’t that be amazing? That’s what’s tantalising,” Arboleda-Velasquez said.

Is it Alzheimer’s? Families want to know, and blood tests may offer answers.

Scientists, including those involved in the research, said the study was far from a definitive explanation of why the man’s memory was protected for years. There could be multiple contributors, rather than a single explanation.

But the possibility that someone could have a high level of protection against decline, even with a brain substantially affected by amyloid and tau buildup, is “intriguing”, said Inmaculada Cuchillo Ibañez, a neuroscientist at the Institute of Neurosciences at Miguel Hernández University in Alicante, Spain. She has studied the reelin protein in the brains of people with more common forms of Alzheimer’s.

“This suggests that this … could be critical in protecting against cognitive impairment,” she said.

The researchers did find an overlap between the two different gene mutations that helped protect these individuals: both mutations affect proteins that bind to the same receptors on the surfaces of brain cells. The scientists also found that mice which are genetically predisposed to develop tau tangles in their brains were less likely to do so when they carried the reelin gene mutation found in the man.

Understanding the possible biochemical pathways that produced protection opens up new approaches for drug development, the researchers said.

Quiroz said the man’s family was excited that something useful had been learned from his case. Patients and researchers are both aware that the disease moves so quickly discoveries may only benefit future generations. But Lopera said these exceptional cases point the way forward.

The two cases, he said, “have enormous potential to benefit the entire world population with or at risk of Alzheimer’s, because they are showing a path to prevention and cure”.

Study details

Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man

Francisco Lopera, Claudia Marino, Anita Chandrahas, Justin Sanchez, Clara Vila-Castelar,  Yakeel Quiroz, et al.

Published in Nature Medicine on 15 May 2023


We characterised the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia–Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signalling in resilience to dementia.


Nature Medicine article – Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (Open access)


The Washington Post article – He defied Alzheimer’s for two decades. Scientists want to know how (Restricted access)


See more from MedicalBrief archives:


Promising results for new Alzheimer’s drug


Australian scientists discover potential therapeutic target for Alzheimer’s


Scientists hail Alzheimer’s breakthrough despite two trial candidates’ deaths


New findings may mean hundreds of thousands misdiagnosed with Alzheimer’s








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