A Dutch study revealed that Alzheimer’s disease occurs in five different variants, each with a specific set of proteins in the cerebrospinal fluid. This finding could explain differences in disease progression and suggest the need for personalized treatments.
Proteins in cerebrospinal fluid reveal five subtypes of Alzheimer’s, but most treatment efforts have focused on just one. (Magic mine/Shutterstock.com)
People with Alzheimer’s disease have different proteins in the fluid surrounding the brain than those without this neurodegenerative condition. However, a study conducted by Dutch scientists on over 400 patients revealed that not all were the same. Five variants of the disease have been identified, each characterized by a specific set of proteins. This could explain the differences in Alzheimer’s progression and suggest the need to treat each variant differently, thus explaining the high failure rate in finding effective treatments so far.
Alzheimer’s is a cruel disease for both patients and their families and can put a strain on healthcare systems due to an aging population. Scientists have tested numerous drugs to combat this condition, but many of them have only been successful in animal models and have failed in human clinical trials.
Some progress has been made recently, with the FDA approving the first new Alzheimer’s drug in 18 years in 2021 and promising results announced last year for the drug donanemab. However, both have problems. Some neuroscientists have long argued that the failure to find an effective treatment is due to the fact that several conditions have been lumped together under the Alzheimer’s label. New research seems to confirm this intuition.
A research team led by Betty Tijms of the Vrije Universiteit Amsterdam analyzed the cerebrospinal fluid of 419 patients diagnosed with Alzheimer’s and 187 controls, focusing on 1058 proteins. The diagnosed patients were divided into three subtypes based on a reduced number of proteins.
Alzheimer’s is associated with the formation of beta-amyloid plaques in the brain, which can be used to diagnose the disease after death. It is therefore not surprising that subtype 1 subjects showed increased amyloid production, along with other distinctive features. Subtype 5, in contrast, had reduced amyloid production and compromised blood-brain barrier, as well as inhibition of nerve cell growth.
Subtype 2 showed excessive pruning of synapses and proteins associated with microglia (immune cells of the brain). Subtype 3, the rarest, had RNA dysregulation, while in subtype 4 the problem appeared to be linked to the choroid plexus, which produces cerebrospinal fluid.
Each subtype had a specific genetic profile that indicated increased risk. For example, subtype 1 was associated with enrichment of the TREM2 gene, previously linked to Alzheimer’s.
If Alzheimer’s has such diverse molecular causes, it makes sense that past attempts to develop an effective treatment have failed. Laboratory animals, selected for their similarity and with common genetic modifications, would probably all replicate the same variant. A molecule that works for one of them might work for the others too. However, when tested on humans, it is only expected to work on a portion of the study group.
Even if a drug were a silver bullet that halted neurodegeneration in all patients with that variant, it might not be enough to demonstrate its value in clinical trials if you don’t have a very large (and expensive) sample. Furthermore, it would be difficult to detect benefits if a drug were harmful to a specific variant, as might happen with amyloid-targeting drugs administered to subtype 5.
Tijms and the other authors may have the solution to this problem. If, by sampling the cerebrospinal fluid of participants in future studies, their variant could be identified, it would be possible to test new drugs specific to each subtype.
These findings may reveal promising new targets for different subtypes. For example, targeting amyloid production appears to be a valid strategy only for subtype 1, while protecting the blood vessels of the brain may be a priority for subtype 5. Subtypes 2 and 5 have a more rapid progression of the disease and an expected shorter-lived than others, important information for future diagnoses.
The study was published in Nature Aging.
Links: nature.com