Alzheimer's, identifying the 5 variants could direct therapies

Alzheimer's is not a single disease, but they exist five different shapes and this could be the key to offering tdifferent and specific erapies based on the type to be treated. the conclusion reached by some Dutch scientists led by Betty Tijms, of the Free University of Amsterdam who in a study published in Nature Aging explain how they managed to identify five variants of Alzheimer's, each associated with one different combination of proteins present in the cerebrospinal fluid that envelops the brain. The discovery is of great importance for research on drugsbecause it could mean that the poor effectiveness of some of those already tested could be due to the fact that they were tested on people suffering from wrong variantscientists hypothesize.

The study: the molecular nuances of the disease

Previous research had already shown that people who develop Alzheimer's disease exhibit differences in protein levels in the cerebrospinal fluid compared to people without the disease. In this new effort, the research team discovered differences in protein levels among patients with the disease.

The researchers then examined 1,058 proteins

present in the cerebrospinal fluid of 419 people suffering from Alzheimer's disease (half of whom already had dementia) and 187 control subjects. Cerebrospinal fluid is a clear, colorless body fluid found in the central nervous system and produced by specialized cells. They thus discovered not only that the protein composition of the fluid of the sick was different from that of the healthy, but that they exist five different molecular gradations of the pathology
. Here they are:

subtype 1 : increased production of
amyloid protein
known to accumulate in the brains of people with Alzheimer's
subtype 2: characterized by excessive pruning of proteins and synapses associated with microglia (the set of immune cells in the brain)
subtype 3: very rare shows lack of RNA regulation
subtype 4: presents dysfunctions of the caroid plexus (where the cerebrospinal fluid)
subtype 5: presents disorders of the blood-brain barrier and reduced levels of amyloid production

Furthermore, the variants differ from each other in various factors, such as the quantity of proteins synthesized, the functioning of the immune system and that of the cells responsible for producing cerebrospinal fluid, but also the speed in which the disease progresses. Furthermore each subtype associated with a precise genetic profile which involves a higher risk of developing the disease.

The implications for drug development

The authors of the study highlight the implications for drug development: for example, those that target the beta-amyloid protein may work in one variant but be harmful in another, or the various forms could present a greater or lesser risk regarding side effects and suggest that treatment for future Alzheimer's patients could begin by first analyzing cerebrospinal fluid to identify the subtype. A drug against amyloid accumulations could in fact help patients with subtype 1, but be useless, or even harmful for patients with subtype 5. In future tests, the authors still suggest, one could first identify the Alzheimer's variant of each patient to try to develop specific drugs for each subtype. However, at the moment it has not been possible to associate the variants with the specific clinical picture of the patients and the road is still long to obtain a specific and targeted therapy on the individual forms.

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