A rare mutation protects against Alzheimer’s disease

So far there is no cure for Alzheimer’s dementia – also because the causes and mechanisms of action have only been partially elucidated. A patient protected from hereditary Alzheimer’s disease by a rare genetic variant now provides more information. He is only the second patient worldwide in whom this protective mechanism has been identified. The effect of its genetic variant provides new insights into the mechanisms of Alzheimer’s disease and could help lead to new treatment approaches.

In Alzheimer’s disease, nerve cells in the brain of sufferers gradually die. The causes of the disease are still not clear. Studies show that plaques of faulty beta-amyloid proteins are deposited between nerve cells. In addition, in Alzheimer’s disease, tau proteins within neurons are pathologically altered and accumulate to form so-called tau fibres. Both processes contribute to the destruction of nerve cells. While the disease usually only occurs at an advanced age, people with a so-called Paisa mutation develop symptoms of the disease at an average age of 44 and usually die around the age of 60 from the consequences of dementia.

Gene variants against Alzheimer’s disease

However, genetic variants can not only increase the risk of developing Alzheimer’s disease, but also reduce it. A team led by Francisco Lopera of the University of Antioquia in Colombia has now identified the second person worldwide who, despite a predisposition to develop 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 Velazquez of Harvard Medical School in Boston.

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His team had already reported in 2019 a carrier of the Paisa mutation, who, despite a genetic predisposition to Alzheimer’s disease, remained symptom-free until she was 70 years old. In this patient, the researchers found that a mutation in the APOE3 gene was responsible for the protection. In search of more information about the development of Alzheimer’s disease, the team screened about 1,200 people with the Paisa mutation — and has now identified another patient who, in addition to this deleterious mutation, carries a “protective mutation” that protects him from decades saved since the onset of the disease.

The second patient worldwide

“Despite the Paisa mutation, the man did not show any cognitive impairment until the age of 67,” say Lubera and his team. He was only diagnosed with mild dementia at the age of 72, and at the age of 73 he participated 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 one illustrate how individuals and extended families with Alzheimer’s disease can help improve our understanding of the disease and open up new avenues for research,” says Lobera’s colleague Yakeel Quiroz.

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 nerve cell function, was modified in his case. Previous research has linked mutations that affect Reelin function to diseases such as schizophrenia, autism and bipolar disorder. On the other hand, the newly discovered mutation does not appear to disrupt Reelin’s function, but rather to increase its effect, as the researchers show in a rat model.

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Protection mechanism revealed

Both Reelin and APOE are altered in patient I in tau protein phosphorylation—albeit in opposite ways. While APOE enhances phosphorylation, Reelin reduces it. “The fact that we found a variant affecting APOE in the first case and Reelin in the second tells us that this signaling pathway, which controls, among other things, tau phosphorylation, could be the key to understanding why these patients were affected,” says Arboleda-Velasquez. Protected.” “This is critical to treatment planning because it clearly shows us that more Reelin can have beneficial effects.”

Brain scans of the shielded patient while he was still alive showed that his brain contained many beta-amyloid plaques, which are typical of Alzheimer’s disease, and that several areas of the brain were also affected by tau fibers. However, the entorhinal cortex, a brain region important for learning and memory, was largely spared. “This case suggests that the interneuron may represent an important small target in protection against dementia,” Queiroz said. Results from the mouse model indicate that the Reelin variant helped protect this important brain region from tau fibers. “The findings can give us clues about where the brain works to delay or stop disease progression, and 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 search for treatments that mimic this protective mechanism. In addition, they hope to find other patients with unusual protective mutations against Alzheimer’s disease in order to gain deeper insights into the disease from these cases.

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Source: Francisco Lopera (University of Antioquia, Colombia) et al., Nature Medicine, Available here. doi: 10.1038/s41591-023-02318-3

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