Diseases that are passed down within families usually have a genetic cause.some are Genetic mutation When inherited, it becomes the direct cause of the disease.Others risk gene It affects the body in a way that increases the likelihood that someone will develop the disease.in Alzheimer’s diseasegenetic mutations in any of three specific genes can cause the disease, and other risk genes increase or decrease the risk of developing Alzheimer’s disease.
Some genetic mutations or variants interact with other genetic changes that cause Alzheimer’s disease. In some cases, genetic changes may interact with the genetic mutations that cause Alzheimer’s disease and prove beneficial. These actually suppress the pathological brain changes that other mutations would normally cause. These protective gene variants can significantly slow or prevent cognitive decline.in two recent case report When it comes to familial Alzheimer’s disease, mutations delayed Alzheimer’s disease symptoms for decades.
I neurologist and neuroscientist He has spent his career researching Alzheimer’s disease and dementia both in the lab and in the clinic. Understanding how genes influence brain chemistry is essential to understanding how Alzheimer’s disease progresses and devising interventions to prevent or slow cognitive decline.
amyloid hypothesis
In the early 1990s, scientists proposed that: amyloid hypothesis Explain how Alzheimer’s disease develops. The first neuropathological changes detected in the brains of Alzheimer’s patients were amyloid plaques – A clump of protein fragments called beta-amyloid. Other changes in the Alzheimer’s brain, such as the accumulation of another type of abnormal protein called neurofibrillary tangles, were thought to develop later in the disease’s progression.
Beta amyloid begins to accumulate in the brain up to 15 years before symptoms appear. Symptoms are correlated with: Number of neurofibrillary tangles In the brain – the more tangles there are, the worse cognition becomes. Researchers have been trying to determine whether preventing or removing amyloid plaques from the brain would be an effective treatment.
Imagine the excitement in the scientific community in the 1990s when researchers identified three different genes responsible for familial Alzheimer’s disease, and all three were involved in beta-amyloid.
The first one is amyloid precursor protein gene. This gene instructs cells to produce amyloid precursor protein, which breaks down into smaller pieces such as beta-amyloid, which forms amyloid plaques in the brain.
The second gene is Presenilin 1, or PSEN-1a protein required to cleave the precursor protein into beta-amyloid.
The third gene is Presenilin 2, or PSEN-2closely related to PSEN-1, is found in a small number of families with familial Alzheimer’s disease.
These findings strengthen the amyloid hypothesis of the disease. but, Uncertainty and opposition to the amyloid hypothesis It has evolved over the past few decades. This was tied in part to the recognition that the neurodegeneration seen in Alzheimer’s disease also involves several other processes, such as neurofibrillary tangles, inflammation, and activation of the immune system.
That hypothesis too received a huge backlash rear many clinical trials Block the effects of amyloid or try to remove it from the brain We’re screwed. In some cases, the treatment caused serious side effects. Some researchers come up with strong defenses That’s the hypothesis. However, uncertainty will remain until definitive results are obtained from clinical trials based on the amyloid hypothesis.
Discovery of genes that influence treatment
The majority – 90 and above – Among Alzheimer’s disease cases, onset occurs later in life, with prevalence gradually increasing from age 65 and older. These cases are mostly sporadic and there is no clear family history of Alzheimer’s disease.
However, a relatively small number of families carry one of the three known gene mutations that cause inheritance of the disease.in familial alzheimer’s disease50% of each generation inherits the mutated gene and develops the disease earlier, usually in their 30s to early 50s.
In 2019 and 2023, researchers identified changes in at least two other genes that significantly delayed the onset of disease symptoms in people with familial Alzheimer’s mutations. These mutated genes were discovered in a very large Colombian family that was predisposed to developing symptoms of Alzheimer’s disease by their 40s.
a family women have a mutated PSEN-1 gene There were no cognitive symptoms. Until she was in her 70s. As a result of her genetic analysis, she has A protein called apolipoprotein E, or ApoE. Researchers believe in a mutation called. Christchurch variation – named after the New Zealand city where the mutation was first discovered – is playing a role in thwarting her disease and slowing its progression.
Importantly, although her brain had large amounts of amyloid plaques, there were very few neurofibrillary tangles. This suggests that the relationship between the two was broken and the number of neurofibrillary tangles was suppressed, slowing the decline in cognitive function.
In May 2023, researchers reported: two brothers from the same extended family They also didn’t develop memory problems until they were in their 60s or late 70s, when researchers found that they had a mutation in a gene that codes for a protein called Reelin.Studies using mice have shown that Reelin Protective effect against amyloid plaque deposition In your brain. The brains of these patients had extensive amyloid plaques, but few neurofibrillary tangles, as in the Christchurch mutation patients. This observation confirms that tangles are the cause of cognitive loss and that there are several ways to “uncouple” amyloid and neurofibrillary tangle accumulation.
Discovering a drug that could mimic the protective effects of the Christchurch or Reelin variants could potentially slow the symptoms of Alzheimer’s disease in all patients. Because the majority of non-familial Alzheimer’s disease occurs after age 70 or 75, delaying the onset of the first symptoms of Alzheimer’s disease by 10 years can have a significant impact on symptoms such as: there is. reduce the spread of disease.
These findings show that the progression of Alzheimer’s disease can be slowed, and may one day lead to further new treatments that can not only treat but also prevent Alzheimer’s disease.
Start and stop
Despite more than 20 years of doubts and treatment failures, recent years have seen positive results from three different treatments (aducanumab, recanemab, and donanemab) that clear amyloid plaques and slow cognitive decline to some extent. is obtained. Although there is still debate as to how much slowing the decline is clinically important, these successes support the amyloid hypothesis. They also suggest that other strategies are needed for optimal treatment.
The U.S. Food and Drug Administration approved the first antibody treatment for Alzheimer’s disease in 2021, Aducanumab, sold under the brand name Aduhelm, controversial. Of his two clinical trials testing safety and efficacy in humans, he has only had positive results in one. The FDA approved this drug based on that single study. Speed up the approval process This could lead to rapid approval of treatments that meet unmet clinical needs.
The secondary antibody is Lecanemab, sold as Leqembiwas approved in January 2023 through the same expedited approval pathway.it was then fully approved In July 2023.
A third antibody, donamab, was successful. Phase 3 clinical trial And we’re waiting for more safety data. Once it is submitted to the FDA, the FDA will consider approving the drug.
This article is republished from conversation Under Creative Commons License.read Original work.
