Challenging established wisdom: The accumulation of Aβ in the brain is linked to Alzheimer's disease

A new study from the USC Leonard Davis School of Gerontology challenges existing ideas that the accumulation of β amyloid (Aβ) in the brain is linked
to Alzheimer's disease.

While the accumulation of amyloid is associated with Alzheimer's-associated neurodegeneration, we know very little about how this protein relates to normal brain aging, said Caleb Finch, senior author of the study and ARCO/William F.
Kieschnick Chair in Geriatric Neurobiology at the University of Southern California's Leonard Davis School
.

To explore levels of Aβ in the human brain, the researchers analyzed tissue samples from
healthy brains and the brains of people with dementia.
The more severe the case of Alzheimer's disease, the higher the Braak stage score, which is a measure
of how widespread the pathological signs of Alzheimer's disease are in the brain.

The analysis showed that the amount of soluble nonfibrinogenic amyloid in the brains of cognitively healthy older adults was similar
to that in Alzheimer's patients.
But, as the researchers expected, Alzheimer's patients have more insoluble β fibrils in their brains, forms of amyloid that clump together to form the "plaques" visible in the disease, said Max Thorwald, the study's lead author and a postdoctoral researcher at the University of Southern California's Leonard Davis School
.

Finch and Thorwald say the finding challenges the idea that
simply having large amounts of amyloid is a potential cause of Alzheimer's disease.
Conversely, an increase in soluble A β may be a general change in the brain associated with aging, rather than being specific to Alzheimer's, and higher levels of amyloid fibrin appear to be a better indicator
of poorer brain health.

Thorwald said Alzheimer's isn't just an increase in the production of a β protein, the more important problem may be a decrease
in the ability to effectively clear protein and avoid amyloid fibrin that forms plaques.

"These findings further support the use of aggregated or fibrous amyloid as a biomarker for Alzheimer's disease treatment
," Thorwald said.
"Amyloid processing occurs at sites where there are fewer precursors and enzymes available for processing, which may indicate that amyloid removal is a key issue
in Alzheimer's disease.
"

The increase in amyloid levels occurs in early adulthood and varies
by brain region.
He added that further research, including those investigating drugs that may break down amyloid, should be combined with positron emission tomography (PET) imaging in healthy individuals and Alzheimer's patients of a wide range of ages to determine how and where amyloid processing and removal change in the brain over time
.

"During human brain aging, the frontal cortex of the brain produces more amyloid than the cerebellum, which coincides
with Alzheimer's-related pathologies in their later years," Thorwald said.
"Future projects should detect amyloid over the course of life in cognitively normal and Alzheimer's patients, by modulating amyloid processing or by removing amyloid through monoclonal antibodies currently used in clinical trials for Alzheimer's disease treatment
.
"

The monoclonal antibody treatment lemanecab, which has been observed in clinical trials to reduce Aβ plaques, was recently approved by the FDA because of its potential to slow cognitive decline in Alzheimer's patients, but the results warrant further careful study of the long-term effects, Finch said
.

"Lecanemab can clearly reduce fibrinogenic amyloid
," he said.
However, we are concerned about major side effects, including brain swelling and bleeding, which are 100% more than in the control group, with unknown delays or potential effects
.
”

Learning more about how the brain processes and clears proteins like Aβ can provide important insights
into Alzheimer's disease and its causes.
Finch noted that few cases of dementia occur with amyloid plaques or aggregated Aβ protein masses, the only pathology
in the brains of affected patients.
Instead, most cases show more complex tissue abnormalities, from extra types of protein accumulation to small bleeding in the brain: "The aging brain is a jungle
.
"

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