Summary: The brains of older, cognitively healthy people have the same amount of soluble non-fibrillar amyloid protein as brains with Alzheimer’s disease. The findings challenge the long-held theory that having higher levels of the amyloid protein is the cause of Alzheimer’s disease.
A new USC Leonard Davis School of Gerontology study challenges existing ideas about how the build-up of a protein called amyloid beta (Aβ) in the brain is linked to Alzheimer’s disease.
While the accumulation of amyloid proteins has been linked to Alzheimer’s-related neurodegeneration, little is known about how these proteins relate to normal brain aging, said University Professor Caleb Finch, senior author of the study and holder of the ARCO/William F. Kieschnick Chair in Neurobiology of Aging at USC Leonard Davis School.
To explore Aβ levels in the human brain, the researchers analyzed tissue samples from healthy brains and the brains of dementia patients. More severe cases of Alzheimer’s are indicated by higher Braak staging scores, a measure of how many signs of Alzheimer’s pathology are found in the brain.
The analysis showed that older, cognitively healthy brains showed the same amount of non-fibrillar amyloid protein as the brains of Alzheimer’s patients. However, as the researchers expected, the brains of Alzheimer’s patients have a higher amount of insoluble Aβ fibrils, a form of amyloid protein that aggregates to form the “plaques” seen in the disease, said Max Thorwald, the study’s first author and a postdoctoral fellow. researcher at the USC Leonard Davis School.
The findings challenge the idea that simply having higher amounts of the amyloid protein in general is the cause of Alzheimer’s, Finch and Thorwald said. However, an increase in soluble Aβ may be a general aging-related change in the brain that is not specific to Alzheimer’s, while higher levels of fibrillary amyloid appear to be a better indicator of poorer brain health.
Rather than Alzheimer’s simply involving increased production of the Aβ protein, the more important problem may be a reduced ability to effectively remove the protein and prevent the creation of fibrillary amyloid that contributes to plaque, Thorwald said.
“These findings further support the use of aggregated, or fibrillary, amyloid as a biomarker for Alzheimer’s treatment,” said Thorwald. “Sites where amyloid processing occurs have less precursors and enzymes available for processing, which may suggest amyloid elimination is a major problem in Alzheimer’s.”
Increases in amyloid levels occur during early adulthood and vary by brain region. Further studies, including those investigating drugs that can destroy amyloid, should combine positron emission tomography (PET) imaging in healthy people and Alzheimer’s patients of various ages to determine how and where amyloid processing and elimination changes in the brain through time. , he added.
“The frontal cortex of the brain has more amyloid production than the cerebellum during the aging process in the human brain, which coincides with Alzheimer’s-related pathology in late life,” Thorwald said.
“Future projects should examine amyloid throughout life in cognitively normal and Alzheimer’s patients by modulating amyloid processing or removing amyloid through monoclonal antibodies currently used in clinical trials for Alzheimer’s treatment.”
The monoclonal antibody treatment Lemanecab has been observed to reduce Aβ plaques in clinical trials and recently received FDA approval for its potential to reduce cognitive decline in Alzheimer’s patients, but these results warrant more careful research on long-term effects, Finch said.
“Lecanemab clearly reduces fibrillar amyloid,” he said. “However, we are concerned with the main side effects, including brain swelling and bleeding, which are 100% more than controls, with unknown delayed or latent effects.”
Learning more about how the brain processes and removes proteins such as Aβ could provide important insights into Alzheimer’s disease and its causes. Finch notes that some cases of dementia occur with amyloid plaques, or aggregated masses of Aβ protein, as the only pathology present in the affected patient’s brain.
However, in most cases there are more complex tissue disorders, from the accumulation of additional types of proteins to small bleeds in the brain: “The aging brain is a forest.”
The study, “Amyloid futures in the pathology of developing brain aging and dementia,” appeared online on December 19, 2022 in the journal. Alzheimer’s and Dementia. Along with Finch and Thorwald, coauthors include Justine Silva and Elizabeth Head of the University of California, Irvine.
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“Amyloid future in the pathology of developing brain aging and dementia” by Max A. Thorwald et al. Alzheimer’s & Dementia
Amyloid futures in the pathology of developing brain aging and dementia
Positron emission tomography (PET) imaging studies of Alzheimer’s disease (AD) patients show a progressive increase in fibrillar Aβ-amyloid. Because current PET ligands degrade nonfibrillar forms, we tested soluble Aβ in AD and controls.
To identify the mechanisms responsible for soluble Aβ in AD brain, we examined lipid rafts (LRs), where amyloid precursor protein (APP) is enzymatically processed.
The frontal cortex is compared to the cerebellum, which has minimal AD pathology. Compared to cognitively normal controls (CTL; Braak 0-1), the elevation of soluble Aβ40 and Aβ42 was similar in middle- and later-stage AD (Braak 2-3 and 4-6).
Clinical grade AD shows a greater increase in soluble Aβ40 than Aβ42 relative to CTL. The LR raft yield per gram of AD frontal cortex was 20% below controls, while cerebellar LR did not differ from Braak score. The extensive overlap of soluble Aβ levels in controls with AD contrasts with PET findings in fibrillar Aβ.
These findings further support fibrillar Aβ as a biomarker for AD treatment and indicate the need for more detailed postmortem analysis of soluble and insoluble Aβ aggregates in relation to PET.