2023-05-18 03:00:04
A team of scientists from Colombia, the USA and Germany has discovered a gene that stops Alzheimer’s. And it has found the brain region that is likely to be particularly important in the treatment.
There are some isolated mountain villages in north-western Colombia where Alzheimer’s occurs earlier in people than anywhere else in the world. In these places in the foothills of the Andes, many people carry a genetic mutation. These people are all descendants of Basque immigrants who came to the country more than 250 years ago and brought the mutation with them. If both parents have the mutation, their child will also have it. If only one parent has the mutation, then the child’s chances are 50 percent.
The average life of a person with the so-called Paisa mutation is as follows: At 44 years of age, the first cognitive impairments, at 49 years of pronounced dementia, at 60 years of death.
Credit: imago/ZUMA Press
We have Francisco Lopero to thank for knowing all this and knowing the background. The now famous neurologist also comes from the Paisa region and has been researching this topic for 30 years. As early as 2019, he reported on a woman who had the mutation but had no symptoms of dementia until she was 70. A notable exception. And now there’s the second of its kind, a man who had no cognitive impairments until the age of 67. Slight dementia began at the age of 72, and the man died at the age of 74 (from another cause). This is a much later course of Alzheimer’s than usual. Why is that?
Credit: imago/ZUMA Press
“What we’ve done with studying these two cases is reading Mother Nature,” says Lopera. “The most exciting thing is that nature has revealed to us both the cause of Alzheimer’s and the cure for it.”
These are insights that might not have been gained without such a cohort of subjects as in north-western Colombia. It is now clear that both people carried a gene that causes Alzheimer’s, but also another one that protected them from the symptoms of the disease for more than two decades. “So the solution,” says Francisco Lopera, “is to mimic nature by developing therapies that mimic the protective mechanisms of these genetic variants in people at risk of developing Alzheimer’s.”
The most exciting thing is that nature has revealed to us both the cause of Alzheimer’s and the cure for it.
Prof. Francisco Lopero, Neurologist, University of Antioquia
Lopera believes that this has opened a big door for the prevention and treatment of incurable diseases. And his colleague Yakeel T. Quiroz, co-author of the now published study, adds: “The insights we are gaining from this second case can give us clues as to where in the brain to target to slow the progression of the disease delay or stop, and they will help us form new hypotheses regarding the sequence of steps that may actually lead to Alzheimer’s dementia.”
Joint research in Colombia, the USA and Germany
The male subject was a participant in a study that is bringing 6,000 people with the known Paisa mutation to Boston for neuroimaging, biomarker and genetic testing. The same study also uncovered the case of the woman carrying two copies of a rare genetic variant affecting APOE3 – a protein strongly linked to Alzheimer’s disease.
However, the researchers were able to rule out the presence of that variant in the male patient. So this time it had to be something different. The most promising candidate was a new and rare variant. The team named it Reelin-COLBOS.
In studies led by Diego Sepulveda-Falla from the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf, the team was able to further verify the protective role of the Reelin-COLBOS variant in mouse models and neuropathological studies.
“Both the APOE-Christchurch and the Reelin-COLBOS cases show a distinct pattern of protection in the post-mortem analyses, one global, the other very local,” explains Sepulveda-Falla. “These outstanding cases teach us that protection from Alzheimer’s disease can take many forms and that therapy may be successful even by targeting key brain structures such as the entorhinal cortex. They force us to overthrow our previous concepts “Rethinking neurodegeneration and cognitive decline. These are exciting times for us and hopefully for Alzheimer’s research as well.”
The researchers refer to Reelin as a “cousin” of the better-known APOE. Both Reelin and APOE compete for binding to similar cellular receptors, jostling for the same spot. “The fact that we found a variant affecting APOE in the first case, and Reelin in the second case, tells us that this signaling pathway, which controls, among other things, the phosphorylation of tau, might be the key to understanding why these patients were protected,” explains study co-author Joseph F. Arboleda-Velasquez. “This is critical for therapy planning because it clearly shows us that more Reelin might potentially have beneficial effects.”
The crucial place in the brain
The neuro-imaging scans in the male subject revealed that while he had a high amyloid beta plaque burden and tau tangles in some brain regions, his entorhinal cortex had very little tau pathology. In other words, there were many Alzheimer’s-triggering deposits in many parts of the brain, but there were significantly fewer in the crucial part.
The entorhinal cortex (also called the limbic association cortex) plays a crucial role in memory and learning, and its degeneration leads to cognitive impairment and dementia. “This case suggests that the entorhinal region may represent a tiny target that is critical in protecting once morest dementia,” said Yakeel T. Quiroz.
As scientists look to explore gene therapies, it is becoming increasingly important to understand which brain region to focus on when administering them. Many treatments for Alzheimer’s disease, including recently FDA-approved drugs and other drugs currently in clinical trials, aim to reduce amyloid plaque build-up. The results of the study point to potential new treatment options, as the two protected patients had extremely high levels of amyloid in their brains and were still protected.
The researchers note that they cannot completely rule out that other factors, including additional gene variants, may have contributed to the patient’s resistance to Alzheimer’s symptoms. But their experimental evidence strongly points to the Reelin-COLBOS variant.
The research group plans to continue their collaborative transnational work to identify more protected patients from these Colombian families and learn from each exceptional case. They are also researching treatment options that target the newly found protective pathway.
The Study “Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man” is in the journal Nature Medicine appeared
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