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Summary: The brains of older, cognitively healthy people have similar amounts of soluble, non-fibrillar amyloid proteins as the brains of those with Alzheimer’s disease. The findings challenge the long-held theory that the presence of higher levels of amyloid proteins is the main 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.
Although the accumulation of amyloid protein is 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 holder of the ARCO/William F. Kieschnick Chair. in Neurobiology of Aging at the USC Leonard Davis School.
To examine the levels of Aβ in the human brain, the researchers analyzed tissue samples from both healthy brains and the brains of dementia patients. More severe Alzheimer’s cases are indicated by higher Braak scores, a measurement 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 the brains of Alzheimer’s patients. But as the researchers expected, the brains of Alzheimer’s patients had higher amounts of insoluble Aβ fibrils, the form of amyloid protein that aggregates to form the telltale “plaques” seen in the disease, said Max Torvald, the study’s first author and postdoctoral researcher at the USC Leonard Davis School.
The findings challenge the idea that simply having higher amounts of amyloid protein in general is a major cause of Alzheimer’s, Finch and Torvald said. Instead, the increase in soluble Aβ may be a general aging-related change in the brain that is not specific to Alzheimer’s disease, while higher levels of fibrillar amyloid appear to be a better indicator of poorer brain health.
Rather than Alzheimer’s simply involving increased production of Aβ protein, the more important problem may be a reduced ability to effectively clear the protein and prevent the creation of fibrillar amyloid, which contributes to plaque, Torvald said.
“These findings further support the use of aggregated or fibrillar amyloid as a biomarker for Alzheimer’s treatment,” Torvald said. “The site where amyloid processing takes place has fewer precursors and processing enzymes available, which may implicate amyloid removal as a key issue during Alzheimer’s.”
The increase in amyloid levels occurs in early adulthood and differs by brain region. Further studies, including those investigating drugs to potentially break down amyloid, should include positron emission tomography (PET) in both healthy subjects and Alzheimer’s patients of a wide age range to determine how and where the processing and removal of amyloid changes in the brain over time, he added.
“The frontal cortex has more amyloid production compared to the cerebellum during the aging process in the human brain, which coincides with the pathologies associated with Alzheimer’s disease in late life,” Torvald said.
“Future projects should examine amyloid across the lifespan in both cognitively normal and Alzheimer’s patients, both by modulating amyloid processing and removing amyloid by monoclonal antibodies currently used in clinical trials to treat Alzheimer’s.”
The monoclonal antibody treatment lemanecab has been observed 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 require further careful study regarding long-term effects, Finch said.
“Lecanemab clearly works to reduce fibrillar amyloid,” he said. “However, we are concerned about major side effects, including cerebral edema and bleeding, which are 100% more than controls, with an unknown delayed or latent effect.”
Learning more about how the brain processes and removes proteins such as Aβ may provide important insights into Alzheimer’s disease and its causes. Finch notes 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 show more complex tissue abnormalities, from the accumulation of extra types of protein to small hemorrhages in the brain: “The aging brain is a jungle.”
The study, “Amyloid Futures in the Expanding Pathology of Brain Aging and Dementia,” appeared online Dec. 19, 2022, in the journal Alzheimer’s and dementia. Along with Finch and Torvald, co-authors include Justin Silva and Elizabeth Head of the University of California, Irvine.
About this Alzheimer’s research news
Original Research: Free access.
“Amyloid futures in the expanding pathology of brain aging and dementia” by Max A. Thorwald et al. Alzheimer’s and dementia
Amyloid futures in the expanding pathology of brain aging and dementia
Positron emission tomography (PET) studies of Alzheimer’s disease (AD) patients show a progressive increase in fibrillar Aβ-amyloid. Because current PET ligands underestimate nonfibrillar forms, we analyzed soluble Aβ in AD and controls.
To identify the mechanisms responsible for soluble Aβ in AD brains, we investigated 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), elevations of soluble Aβ40 and Aβ42 were similar for intermediate and later stage AD (Braak 2-3 and 4-6).
AD with clinical grade showed a greater increase in soluble Aβ40 than Aβ42 against CTL. LR raft yield per gram of AD frontal cortex was 20% below that of controls, whereas cerebellar LR did not differ by Braak score. The wide overlap of soluble Aβ levels in AD controls contrasts with PET findings for fibrillar Aβ.
These findings further support fibrillar Aβ as a biomarker for AD treatment and indicate the need for more detailed postmortem analysis of various soluble and insoluble Aβ aggregates in conjunction with PET.
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