2023-05-16 09:42:47
So far there is no cure for Alzheimer’s dementia – also because the causes and mechanisms of action have only been partially clarified. A patient who is protected from hereditary Alzheimer’s by a rare genetic variant now provides more information. He is only the second patient worldwide in whom such a protective mechanism has been identified. The effect of his gene variant provides new insights into the mechanisms of Alzheimer’s disease and could help to find new treatment approaches.
In Alzheimer’s, the nerve cells in the brain of those affected gradually die. The causes of the disease are still unclear. Studies show that plaques of misfolded amyloid beta proteins are deposited between nerve cells. In addition, in Alzheimer’s, the tau proteins inside the nerve cells are pathologically altered and accumulate to form so-called tau fibrils. Both processes contribute to the destruction of nerve cells. While the disease usually only occurs at an advanced age, people with the so-called Paisa mutation develop symptoms of the disease at an average age of 44 and usually die at around the age of 60 from the consequences of dementia.
Genetic variants against Alzheimer’s
However, genetic variants can not only increase the risk of Alzheimer’s, but also reduce it. A team led by Francisco Lopera from the University of Antioquia in Colombia has now identified the second person worldwide who, despite being predisposed to Alzheimer’s, was protected from the disease by an additional mutation. “The genetic variant we identified points to a pathway that may lead to extreme resilience and protection against Alzheimer’s symptoms,” says co-author Joseph Arboleda-Velasquez of Harvard Medical School in Boston.
His team had already reported in 2019 on a carrier of the Paisa mutation who, despite her hereditary predisposition to Alzheimer’s, remained symptom-free until she was 70. In this patient, the researchers found that a mutation in the APOE3 gene was responsible for the protection. In search of further insight into the development of Alzheimer’s disease, the team examined around 1,200 people with the Paisa mutation – and has now actually identified another patient who, in addition to this harmful mutation, carried a “protective mutation” that has protected him for decades saved from the onset of the disease.
Second patient worldwide
“Despite the Paisa mutation, the man showed no cognitive impairments up to the age of 67,” report Lopera and his team. He was only diagnosed with mild dementia at the age of 72, and at the age of 73 he took part in a neurological examination as part of the study. A year later he died of pneumonia and his family agreed to donate his brain for research. “Extraordinary cases like this illustrate how individuals and extended families with Alzheimer’s can help improve our understanding of the disease and open new avenues for research,” says Lopera’s colleague Yakeel Quiroz.
The examinations showed that the man, unlike the first patient, did not have any mutations in the APOE3 gene. Instead, the gene for the protein Reelin, which plays an important role in the function of nerve cells, was modified in his case. Previous research has linked mutations that affect reelin function to diseases such as schizophrenia, autism and bipolar disorder. The newly discovered mutation, on the other hand, does not appear to disrupt the function of Reelin, but rather to increase its effect, as the researchers demonstrated in a mouse model.
protective mechanism revealed
Both Reelin and the APOE altered in the first patient are involved in the phosphorylation of the tau protein – albeit in opposite ways. While APOE promotes phosphorylation, Reelin decreases it. “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, could be the key to understanding why these patients are affected.” were protected,” says Arboleda-Velasquez. “This is crucial for therapy planning because it clearly shows us that more Reelin could potentially have beneficial effects.”
The brain scans performed on the protected patient while he was still alive showed that his brain had many amyloid beta plaques, typical of Alzheimer’s, and that several brain regions were also affected by tau fibrils. However, his entorhinal cortex, a brain region important for learning and memory, was largely spared. “This case suggests that the entorhinal region may represent a tiny target that is critical in protecting against dementia,” Quiroz said. Results from the mouse model suggest that the Reelin variant helped protect this important brain region from tau fibrils. “The findings can give us clues as to where in the brain to act to delay or stop the progression of the disease, and they will help us form new hypotheses about the sequence of steps that actually lead to Alzheimer’s dementia .”
In future studies, the team plans to look for treatments that mimic this protective mechanism. In addition, they hope to find other patients with unusual protective mutations against Alzheimer’s in order to gain deeper insights into the disease from these cases.
Source: Francisco Lopera (University of Antioquia, Colombia) et al., Nature Medicine, two: 10.1038/s41591-023-02318-3
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