Alois Alzheimer was a neuroanatomist and psychiatrist in 1906. reported “a peculiar severe disease process of the cerebral cortex” to a gathering of psychiatrists in Tübingen, Germany.
The case was a 50-year-old woman who suffered from memory loss, delusions, hallucinations, aggression, and confusion – all of which worsened until her untimely death five years later.
Alzheimer was found to have distinct plaques in her brain during an autopsy. These plaques – clumps of amyloid-beta protein – are still considered to be the cause of Alzheimer’s disease.
This theory however has two problems.
It doesn’t explain why so many people, even old ones, have plaques in their brains despite not having any neurological symptoms such as memory loss.
Second, Clinical trials for drugs that reduce these plaques have been unsuccessful – with one recent exceptionBut more on that later.
Amyloid-beta protein is able to accumulate in the form plaques (insoluble lumps), and then the original soluble form, which performs important brain functions, is destroyed.
Some studies have shown that reduced levels of soluble amyloid-beta – called amyloid-beta 42 – have led to patients having worse clinical outcomes.
In a Recent studyPublished in Journal of Alzheimer’s DiseaseWe investigated whether amyloid beta 42 or brain plaques are more important for Alzheimer’s disease progression.
This question was answered by studying data on people with an inherited rare gene mutation that places them at high risk for developing Alzheimer’s disease. Participants were from the Dominantly Inherited Alzheimer Network cohort study.
The depletion amyloid Beta 42 (the functional form of amyloid Beta) was more dangerous than the accumulation of plaques (the insoluble amyloid beta clumps).
On average, participants were followed up for three years. We found those with high levels in amyloid beta 42 (the liquid surrounding the brain and spinal cord) were well protected. Their cognition was also preserved during the study period.
This is consistent with numerous studies that demonstrated important functions of amyloid beta 42 in Memory and cognition.
It is also pertinent because we examined people with Alzheimer’s who were affected by the genetic mutation. This group provides the strongest evidence to support the hypothesis that amyloid-beta is harmful.
However, cognitive function was maintained in all cases, regardless of brain plaques.
It is also worth mentioning that in some rare, inherited forms of Alzheimer’s disease – for example, in carriers of the so-called Osaka gene mutation or Arctic mutation – people can develop dementia having low levels of amyloid-beta 42 and no detectable plaques.
This suggests that plaques don’t cause dementia. However, low levels of amyloid Beta 42 may be.
Lecanemab – the one recent exception
How will our findings impact drug development and clinical trials of Alzheimer’s diseases? The most recent trial with lecanemabAnonymous AntibodyDrug that reduces plaques has been rejected in all Alzheimer’s drug trials.
A few drugs were developed to reduce levels of amyloid Beta 42. They are based on the belief that patients with fewer plaques will have their normal protein levels lower. However, many of these drugs made patients’ conditions worse. It could get worse.
Recent reports have shown that Lecanemab has a modest but important effect on cognitive decline. According to previous studiesThe drug also increases levels of amyloid Beta 42 in CSF.
This again is in line with our hypothesis that an increase in normal amyloid protein could be beneficial.
More information will be available when the results from the lecanemab trial have been published. We currently have no information. Press releaseThe drug manufacturer.
For future trials, we believe it will be crucial to examine the levels of Amyloid-beta 42. It is important to determine if it is better to increase or restore it to normal values than to remove it.
This could be achieved using proteins similar to amyloid-beta 42 – so-called “protein analogs” – but that clump together less than the natural ones.
The active protein replacement approach could offer a promising alternative to Alzheimer’s or other protein aggregation disease, such as Parkinson’sMotor neuron disease.
Andrea SturchioClinical Neuroscience, MD, PhD Student Karolinska Institutet; Kariem EzzatLaboratory Medicine, Research Scientist Karolinska InstitutetAnd Samir EL. AndaloussiProfessor of Laboratory Medicine Karolinska Institutet
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