Reduced proteins associated with Alzheimer's disease, not amyloid plaques

A new study from the University of Cincinnati supports the hypothesis that Alzheimer's disease is caused by a drop in the level of a particular protein, contrary

UC researchers, led by Alberto Espay, MD, and Andrea Sturchio, MD, in collaboration with the Karolinska Institute in Sweden, published the study

The study focused on a protein

For more than 100 years, the traditional view in the field of Alzheimer's research has been that Alzheimer's disease is caused

Esper, a professor of neurology at the University of California School of Medicine, James and director of the Gardner Family Center for Parkinson's Disease and Movement Disorders at the University of California, said: "Paradoxically, as we age, many of us accumulate plaque in the brain, but very few develop dementia

Sturchio noted that over the years, many studies and clinical trials have aimed to reduce amyloid plaques in the brain, and some have reduced plaques, but none of them slowed the progression

"I think this is probably the best evidence that lowering levels of soluble forms of protein can be toxic," said

The team's previous research has 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, while people with low levels of soluble amyloid – β are more likely to have cognitive impairment

In the current study, the research team analyzed amyloid-β levels in a group of patients with mutations that predict overexpression of amyloid plaques in the brain that are thought to be more likely to cause Alzheimer's disease

Sturchio said: "One of the strongest supports for the amyloid toxicity hypothesis is based on these mutations

Even in this group of patients who are considered to be at the highest risk of developing Alzheimer's, the researchers found similar results

"We found that those who had already accumulated plaque in their brains had a lower

The study found that when baseline levels of soluble amyloid-β in the brain were above 270 pig per milliliter, people could maintain cognitive normalcy

"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, not the amyloid plaque we get," Espey said

Sturchio said the study is further investigating whether increasing levels of soluble amyloid-β in the brain is a beneficial treatment
for Alzheimer's patients.

Espe says it's important to make sure that elevated levels of proteins introduced into the brain don't turn into amyloid plaques, because normal function requires a soluble version of this protein to have an impact on
the brain.

On a larger scale, the researchers say they believe similar hypotheses that lead to neurodegenerative degeneration can be applied to other diseases, including Parkinson's and Creutzfeldt-Jakob disease, and research in these areas continues
.

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
.
"

Espe said 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 levels of soluble amyloid – β, which most other anti-amyloid treatments
can't do," Esper said.

Or, precision medicine needs to have a deeper understanding of what causes soluble amyloid – β levels to drop, whether it is a virus, toxin, nanoparticle, or biological or genetic process
.
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.

Espe said precision medicine will provide a more personalized treatment
taking into account the fact that no two patients are similar.
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.

Espay said: "The Cincinnati Cohort Biomarker Project is committed to the first success
of deploying precision medicine in this decade.
" "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.
"