Contrary to the prevailing view: Alzheimer's disease is not an increase in specific proteins, but a decrease

The currently popular theory is that Alzheimer's disease is caused
by the accumulation of amyloid plaques in the brain.
However, new research has found that it is actually caused
by a drop in the level of a particular protein.

Contrary to the mainstream theories that have recently been questioned, a new study from the University of Cincinnati (UC) supports the hypothesis that Alzheimer's disease is caused
by a drop in the level of a particular protein.

UC researchers, led by Alberto Espay, MD, and Andrea Sturchio, MD, in collaboration with the Karolinska Institute in Sweden, published the study
in the Journal of Alzheimer's Disease on October 4, 2022.

The study focused on a protein
called β amyloid.
This protein normally performs functions in the brain in a soluble form, meaning it can be soluble in water
.
However, it sometimes hardens into chunks, called amyloid plaques
.

"I think this is probably the best evidence that reducing the soluble form of
protein can be toxic.
" After the operation, the patient's condition worsened
.
—Andrea Sturchio, M.
D

For more than 100 years, the traditional view in the field of Alzheimer's research has been that Alzheimer's disease is caused
by the accumulation of amyloid plaques in the brain.
However, Espay and his colleagues hypothesized that plaques were actually just the result
of a drop in levels of soluble amyloid-β in the brain.
These levels drop because normal proteins are converted to abnormal amyloid plaques
under biological, metabolic, or infectious stress.

"Paradoxically, as we age, plaque accumulates in the brains of many people, but very few develop dementia
," Espay said.
However, plaque remains at the center of our attention as it relates
to the development of biomarkers and treatment strategies.
”

Sturchio noted that over the years, many clinical trials and research studies have aimed to reduce amyloid plaque
in the brain.
Some drugs have been successful in reducing plaque, but it wasn't until Sept.
27, when Lecanemab announced a positive trial, that it really slowed the progression
of Alzheimer's disease.
What's more, to support their hypothesis, clinical outcomes for patients have worsened
in a number of clinical trials that reduce levels of soluble amyloid-β.

Sturchio said: "I think this is probably the best evidence that reducing the soluble form of
protein can be toxic.
" He is the first author of the report and an adjunct research lecturer
at the University of California School of Medicine.
"After the operation, the patient's condition deteriorated
.
"

The team's previous research found that people with high levels of soluble amyloid — β — are more likely to have cognitive impairment regardless of the build-up of plaque in the brain, but people with low levels of soluble amyloid β are more likely to have cognitive impairment
.

In the current study, the research team examined levels of amyloid-β in a group of patients whose genetic mutations predict overexpression of amyloid plaques in the brain that are thought to make them more likely to develop Alzheimer's
.

Sturchio said: "One of the strongest supports for the amyloid toxicity hypothesis is based on these mutations
.
We studied this group because it provides the most important data
.
”

Even in this group of patients who are considered to be at the highest risk of developing Alzheimer's, the scientists observed similar results
to those found in the general population.

"We found that those who had already accumulated plaque in their brains had a lower
risk of developing dementia over a three-year period if they were able to produce high levels of soluble amyloid – β," Espay said.

Studies have found that regardless of the number of amyloid plaques in the brain, as long as the baseline level of soluble amyloid – β in the brain remains above 270 pig per milliliter, people can maintain cognitive normality
.

"If you deviate from the bias that we've created for too long that the neurodegenerative process is caused by the amyloid we lose — β, rather than the amyloid plaque we get," Espay said
.
Degradation is a process of loss, and it turns out that what we lose is much more
important.
”

According to Sturchio, research is moving forward to investigate whether increasing levels of soluble amyloid-β in the brain is a beneficial treatment
for Alzheimer's patients.
It must be ensured that elevated levels of proteins entering the brain do not turn into amyloid plaques, as normal functioning requires a soluble version of this protein to affect
the brain.

On a larger scale, the research team believes that similar hypotheses that lead to neurodegenerative degeneration can be applied to other diseases, including Parkinson's and Creutzfeldt-Jakob disease
.
Research in these areas is also ongoing
.

In Parkinson's disease, for example, a normally soluble protein in the brain called α-synuclein hardens into a precipitate called
Lewy's body.
The researchers hypothesized that Parkinson's disease is not caused by the aggregation of Lewy bodies in the brain, but by a decrease in normal soluble α-synuclein levels
.

"We argue that in all degenerative diseases, it may be more meaningful to lose normal proteins than the parts
of the measurable abnormal protein," Espay said.
"As these diseases progress, the brain continues to atrophy, and the end result is a decrease in protein rather than an increase
.
"

He envisions two ways to treat neurodegenerative diseases in the future: rescue medicine and precision medicine
.
Rescue medicine seems to be the current job, studying whether raising levels of key proteins, such as amyloid – β, leads to better outcomes
.

"Interestingly, the anti-amyloid drug lecanemab has recently been reported to be beneficial, in addition to reducing amyloid, it also raises the level of soluble amyloid - β, which most other anti-amyloid treatments
cannot do," Espay said.

Or, precision medicine needs to gain a deeper understanding of what causes soluble amyloid – β levels to decline, whether it's viruses, toxins, nanoparticles, or biological or genetic processes
.
If the root cause is addressed, the level of this protein does not need to be increased, as the conversion
from a soluble normal protein to an amyloid plaque does not occur.

Espay said precision medicine will take into account the fact that no two patients are exactly the same, allowing for a more personalized treatment
.
Through the Cincinnati Cohort Biomarker Program, researchers are making progress
in the field of precision medicine.
The program aims to classify neurodegenerative diseases by biological subtype in order to match
biomarker-based treatments with those most likely to benefit from.

"The Cincinnati Cohort Biomarker Project is committed to the first success
of deploying precision medicine in this decade," Espay said.
By identifying biological, contagious and toxic subtypes of Parkinson's and Alzheimer's, we will have specific treatments that can slow the progression of
these diseases.
”

High Soluble Amyloid-?42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations" by Andrea Sturchio, Alok K.
Dwivedi, Tarja Malm, Matthew J.
A.
Wood, Roberto Cilia, Jennifer S.
Sharma, Emily J.
Hill, Lon S.
Schneider,Neill R.
Graff-Radford, Hiroshi Mori, Georg Nübling, Samir El Andaloussi, Per Svenningsson, Kariem Ezzat, Alberto J.
Espay and the Dominantly Inherited Alzheimer Consortia (DIAN), 16 September 2022, Journal of Alzheimer’s Disease.