People with partial resistance to Alzheimer’s could inspire new drugs

A minority of people with partial resistance to Alzheimer’s disease is causing a rethinking of the biological causes of Alzheimer’s disease, which could lead to new treatments.

Their experience suggests that a protein called tau, which accumulates in the brain cells of Alzheimer’s patients, may be as important or even more important than the current prime suspect, a protein called beta-amyloid. are doing.

Drugs are under development that aim to reduce memory loss and confusion in Alzheimer’s disease by lowering amyloid levels, but their effects are so small that in practice they may not provide more cost-sensitive health care services. may not be approved for use in countries where .

People with partial resistance to Alzheimer’s disease are part of a community living in Colombia who have high levels of a dangerous genetic mutation called Alzheimer’s disease. PSEN1-280A, was discovered in the 1980s. This variant is believed to have been introduced by the Spanish conquistadors in the 17th century. People with this disease live in isolated areas of the Andes Mountains and spread to about 25 families.

The gene, which encodes an enzyme involved in the production of amyloid, was thought to inevitably lead to Alzheimer’s disease in people with one copy of the dangerous mutation in their 40s.

But in 2019, a woman was found who not only carried a deleterious mutation, but also two copies of a second, rare variant called Christchurch in another gene. Juvenile Alzheimer’s disease. Instead, she didn’t develop dementia until she was in her 70s.

Now, Diego Sepulveda Falla of the Hamburg-Eppendorf University Medical Center in Germany and his colleagues found a second similar case while studying this Colombian community. It is a Colombian male who carries both deleterious mutations. PSEN1-280A One copy of another rare variant called Lerun Corbos. This also provided partial protection, as he developed Alzheimer’s disease in his 70s as well.

“Once it might be a coincidence, but twice it sounds something different,” says Sepulveda Falla. “It is possible that protected cases have not yet been discovered.”

Both men and women had extensive accumulation of amyloid in the brain. PSEN1-280AHowever, their tau levels were lower than those normally seen in Alzheimer’s disease. This suggests that high tau is primarily responsible for the symptoms of amnesia and confusion.

“Tau is more important.” [than amyloid]says Sepulveda Falla. “I think we have enough evidence to say that.”

The man also had a sister with a deleterious mutation and one copy of the newly discovered protective mutation. When she was 64 and had her first check-up, she seemed a little sheltered because she had severe dementia.

In another study, the researchers found that several members of the Colombian community carried one copy of the Christchurch protective mutation and the high-risk Alzheimer’s-type mutation, according to Sepulveda Falla. The onset of dementia appears to be moderately delayed. .

“This seems to be a pretty dose-dependent effect,” he says, because the woman who had two copies of Christchurch took a long time to improve. Another study has not yet been published, so details are unknown.

Two protective gene variants affect tau in different ways. Brain cell damage in Alzheimer’s disease is usually associated with the accumulation of tau that is chemically modified in a process called phosphorylation.

When a team gives protection Lerun Corbos Introduction of the genetic mutant into mice reduced tau phosphorylation.

Interestingly, women with the Christchurch mutation had lower whole-brain phosphorylated tau levels, whereas men with the Christchurch mutation had Lerun Corbos Mutants lacked phosphorylated tau in a small part of the brain called the entorhinal cortex. It is located on each side of the head, next to the hippocampus, the memory center of the brain.

Early stages of Alzheimer’s disease are thought to initiate the accumulation of tau in the entorhinal cortex.

“fact [the man] By reducing phosphorylation in this specific region, we were able to delay the onset of damage by 30 years, which is a very important finding,” says Stephanie Fowler of University College London.

Fowler said there are treatments in development called antisense oligonucleotides that reduce the production of tau by cells. “If only this area can be protected, that seems to be enough.”

Richard Oakley of the Alzheimer’s Association, a British charity, said the findings support the idea that amyloid is an important cause of the condition, but not the only factor. rice field. “Understanding this kind of resilience may highlight other targets for future drugs,” he says.

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