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New study challenges previous ideas about Alzheimer's disease

Summary: The brains of older, cognitively healthy people have similar amounts of dissolvable, non-fibril amyloid proteins as the brains of those with Alzheimer’s disease. The findings challenge the long-held theory that having higher levels of amyloid proteins is an underlying cause of Alzheimer’s disease.

Source: USC

A new study from the USC Leonard Davis School of Gerontology challenges existing ideas of how accumulation of a protein called beta-amyloid (Aβ) in the brain is related to Alzheimer’s disease.

Although accumulation of amyloid protein has been linked to Alzheimer’s-related neurodegeneration, little is known about how the protein relates to normal brain aging, said University Professor Caleb Finch, senior author of the study and ARCO/William F Chair. Kieschnick in the Neurobiology of Aging at the USC Leonard Davis School.

To explore Aβ levels in the human brain, researchers analyzed tissue samples from both healthy brains and those from patients with dementia. More severe cases of Alzheimer’s were indicated by higher Braak staging scores, a measure of how widely signs of Alzheimer’s pathology are found in the brain.

The analysis revealed that older, cognitively healthy brains showed similar amounts of soluble, non-fibrillar amyloid protein as brains from Alzheimer’s patients. But as the researchers expected, the brains of Alzheimer’s patients had increased amounts of insoluble Aβ fibrils, the form of amyloid protein that aggregates to form the telltale “plaques” seen in the disease, said Max Thorwald, the study’s first author and postdoctoral fellow. -doctoral research fellow at USC Leonard Davis School.

The findings challenge the idea that simply having higher amounts of amyloid protein in general is an underlying cause of Alzheimer’s, say Finch and Thorwald. Rather, the increase in soluble Aβ may be a general age-related change in the brain not specific to Alzheimer’s disease, whereas higher fibrillar amyloid levels appear to be a better predictor of poorer brain health.

Rather than Alzheimer’s simply involving increased production of the Aβ protein, the more important issue may be a reduced ability to effectively clear the protein and prevent the creation of fibrillar amyloid that contributes to plaque, Thorwald said.

“These findings further support the use of aggregated or fibrillar amyloid as a biomarker for Alzheimer’s treatments,” said Thorwald. “The site where amyloid processing occurs has less precursor and enzyme available for processing, which may suggest amyloid clearance as a key issue during Alzheimer’s disease.”

Increases in amyloid levels happen during early adulthood and differ by brain region. Additional studies, including those investigating drugs to possibly break down amyloid, should incorporate positron emission tomography (PET) imaging in healthy subjects and Alzheimer’s patients of a wide range of ages to determine how and where amyloid processing and the removal changes in the brain over time, he added.

“The frontal cortex of the brain has more amyloid production compared to the cerebellum during the aging process in the human brain, which coincides with pathologies correlated with Alzheimer’s later in life,” said Thorwald.

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To explore Aβ levels in the human brain, researchers analyzed tissue samples from both healthy brains and those from patients with dementia. The image is in the public domain

“Future projects should examine amyloid across the lifespan in cognitively normal and Alzheimer’s patients with modulation of amyloid processing or amyloid clearance via monoclonal antibodies currently used in clinical trials for the treatment of Alzheimer’s.”

Lemanecab monoclonal antibody treatment has been shown to reduce Aβ plaques in clinical trials and recently received FDA approval for its potential to slow cognitive decline in Alzheimer’s patients, but the results warrant more careful research into the long-term impact. term, said Finch.

“Lecanemab clearly works to decrease fibrillar amyloid,” he said. “However, we are concerned about major side effects, including brain swelling and bleeding, which were 100% greater than in controls, with latent or latent impact unknown.”

Learning more about how the brain processes and removes proteins like Aβ can provide important information about Alzheimer’s disease and its causes. Finch noted that very few cases of dementia occur with amyloid plaques, or masses of aggregated Aβ protein, as the only pathology present in the brains of affected patients.

Instead, most cases have more complicated tissue abnormalities, from the accumulation of additional types of protein to small bleeds in the brain: “The aging brain is a jungle.”

The study, “Future amyloids in the expanding pathology of brain aging and dementia,” appeared online Dec. Alzheimer’s and Dementia. Along with Finch and Thorwald, coauthors include Justine Silva and Elizabeth Head of the University of California, Irvine.

About This Alzheimer’s Research News

Author: Press office
Source: USC
Contact: Press Office – USC
Image: The image is in the public domain

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“Amyloid futures in the expanding pathology of brain aging and dementia” by Max A. Thorwald et al. Alzheimer’s and Dementia


Summary

Future amyloids in the expanding pathology of brain aging and dementia

Positron emission tomography (PET) imaging studies of patients with Alzheimer’s disease (AD) show progressive increases in fibrillar Aβ-amyloid. As current PET ligands underestimate non-fibrillar forms, we analyzed soluble Aβ in AD and controls.

To identify the mechanisms responsible for soluble Aβ in AD brains, we examined lipid rafts (LRs), where amyloid precursor protein (APP) is enzymatically processed.

The frontal cortex was compared with the cerebellum, which has minimal AD pathology. Compared to cognitively normal controls (CTL; ​​Braak 0-1), soluble Aβ40 and Aβ42 elevations were similar for intermediate- and advanced-stage AD (Braak 2-3 and 4-6).

Clinical grade AD showed a greater increase in soluble Aβ40 than Aβ42 relative to CTL. The LR raft yield per gram of AD frontal cortex was 20% lower than controls, while the cerebellar LR did not differ by Braak score. The extensive overlap of soluble Aβ levels in AD controls contrasts with the PET findings in fibrillar Aβ.

These findings further support fibrillar Aβ as a biomarker for AD treatments and show the need for more detailed post mortem analyzes of diverse soluble and insoluble Aβ aggregates versus PET.