There is not just one Alzheimer’s: there are at least five. And even if this awareness will extend the time and increase the power of the work in search of an effective cure, the good news is that this unexpected discovery could put dozens of drugs and therapies previously discarded because they were mistakenly considered inefficient or not very effective. .
Alzheimer’s is a diabolical puzzle of genes. But we are starting to put the pieces in place by Valentina Arcovio 05 January 2024
And give
According to estimates from the Dementia Observatory of the Istituto Superiore di Sanità, there are 600 thousand Alzheimer’s patients in Italy. Globally, dementia affects 55 million people, but this is a figure that is growing on a daily basis, with forecasts reaching 78 million by 2030. A step forward in understanding how the disease described for the first time in 1906 by the neuropathologist works. Alois Alzheimer was made last year, when it was understood that the accumulation of amyloid beta and tau proteins that lead to cognitive decline is associated with impaired energy production at the cellular level.
As we age, mitochondria no longer function as they should, thus compromising some fundamental processes for the nerve cell. This, however, only answered part of the question.
Alzheimer’s, the therapy of the future comes from the mitochondria by Noemi Penna 11 April 2023
Research
Once the accumulation of plaques in the brain has begun, each decline is different: other biological processes come into play, such as inflammation and the growth of nerve cells. Now, using new cerebrospinal fluid analysis techniques, scientists from the Alzheimer Center in Amsterdam and Maastricht University have been able to measure the impact of other processes that influence neurodegenerative progression and discovered that there are at least five variants biological mechanisms of the disease, characterized by as many possible treatment options.
Five variants of Alzheimer’s
Nello study just published in Nature Aging, Betty Tijms e Pieter Jelle Visser examined 1058 proteins in the cerebrospinal fluid of 419 people with Alzheimer’s disease, which led to them being divided into five disease variants that differ in the degree of protein synthesis, the functioning of the immune system, the production of the cerebrospinal fluid and the dysregulation of the ‘RNA, which leads to a more or less early onset and a more or less rapid and disabling course.
The two most common variants are characterized by increased amyloid production and a disrupted blood-brain barrier, with less nerve cell growth. Substantial characteristics that have great importance for treatment strategies and drug research, given that a molecule could work well on one variant of the disease, but be completely ineffective for another.
What changes
The discovery of these five variants – but there could be even more, given that this dementia affects something like 44 million people worldwide – changes the rules of the game. This is because first of all it will be necessary to create a reliable test to know which variant you belong to, and then start a series of specific trials for each molecular subtype, which has distinct genetic risk profiles, also taking into consideration molecules that had been discarded because ineffective in counteracting the accumulation of myloid beta and tau proteins.
“For example, drugs that inhibit amyloid production may work in the variant with increased amyloid production, but may be harmful in the variant with reduced production – explain the authors -. It is also possible that patients with a variant have a higher risk of side effects, while that risk is much lower with others. The next step for our research group will be to demonstrate how Alzheimer’s variants actually react differently to drugs, so that we can treat everyone in the future with appropriate medications”.
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The challenge for researchers: each Alzheimer’s has its own therapy
Needless to say, times will get longer: researchers now find themselves faced with the challenge of finding a cure not for one Alzheimer’s, but for five different ones. And all the research conducted so far that has not taken into account the distinct genetic risk profiles should also be reviewed.
“Cerebrospinal fluid is the most accessible biofluid to study the molecular complexity of neurodegenerative diseases throughout life. It is in close contact with the brain, and protein concentrations in CSF reflect ongoing pathophysiological processes. Subtype-specific molecular alterations appear be present already at a very early stage, when cognition is still intact and neuronal damage is limited.” This opens up the possibility of subjecting each suspected case to a CSF sample via a lumbar puncture, to actually ascertain whether it is Alzheimer’s and which variant.
The diagnosis
Even a functional magnetic resonance imaging is able to highlight the differences, given that “the cases differ in the degree and anatomical position of the cortical atrophy”, but this examination can only refute an advanced state of the disease. “This shows us that subtyping based on cerebrospinal fluid can be useful for selecting individuals for a specific therapeutic treatment, both for subject stratification and for the analysis of responders and side effects in clinical trials. But the next studies – conclude Betty Tijms and Pieter Jelle Visser – they will first of all have to re-analyse the proteomics in the samples from the research already carried out, to verify whether particular treatments have specific effects based on the subtype to which one belongs”.
Alzheimer’s, how diet influences the risk of dementia by Barbara Orrico 28 December 2023