A new study challenges previous ideas about Alzheimer’s disease
A new study challenges previous ideas about Alzheimer’s disease
Abstract: The brains of older, cognitively healthy people have similar amounts of soluble, non-fibrillar amyloid proteins as the brains of Alzheimer’s patients. The findings challenge the long-held theory that high levels of amyloid proteins are the root cause of Alzheimer’s disease.
A new study from the USC Leonard Davis School of Gerontology 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 the neurodegeneration associated with Alzheimer’s disease, little is known about how the protein is related 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 to the Leonard Davis School of USC.
To investigate Aβ levels in human brains, the researchers analyzed tissue samples from healthy brains and brains from dementia patients. More severe cases of Alzheimer’s disease were indicated by higher Braak stage scores, a measurement of how widespread signs of Alzheimer’s pathology are 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, a form of amyloid protein that accumulates into the telltale “plaques” seen in the disease, said Max Thorwald, the study’s first author and a postdoctoral researcher at USC Leonard Davis School.
These findings challenge the idea that higher amounts of amyloid protein are generally the underlying cause of Alzheimer’s disease, Finch and Thorwald said. Instead, an increase in soluble Aβ may be a general age-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 formation of fibrillar amyloid that contributes to plaque, Thorwald said.
“These findings further support the use of aggregated or fibrillar amyloid as a biomarker for the treatment of Alzheimer’s disease,” Thorwald said. “The site where amyloid processing takes place has fewer precursors and enzymes available for processing, which may suggest amyloid clearance as a key issue during Alzheimer’s disease.”
Increases in amyloid levels occur during early adulthood and vary by brain region. Further studies, including those investigating drugs to potentially break down amyloid, should include positron emission tomography (PET) imaging in healthy individuals and Alzheimer’s patients of a wide age range to determine how and where amyloid processing and removal changes in the brain during time, he added.
“The frontal cortex of the brain produces more amyloid compared to the cerebellum during the aging process in the human brain, which coincides with their pathologies associated with Alzheimer’s disease in late life,” said Thorwald.
“Future projects should examine amyloid throughout life in both cognitively normal patients and Alzheimer’s patients, with modulation of amyloid processing or amyloid removal via monoclonal antibodies currently used in clinical trials to treat Alzheimer’s disease.”
Monoclonal antibody treatment lemanecab 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 require further careful research regarding long-term effects, Finch said.
“Lekanemab clearly works to reduce fibrillar amyloid,” he said. “However, we are concerned about major side effects, including brain swelling and bleeding, which were 100% higher than in controls, with an unknown delayed or latent effect.”
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 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 represent more complicated tissue abnormalities, from the accumulation of extra types of proteins to small brain bleeds: “The aging brain is a jungle.”
The study, “The Future of Amyloid in the Emerging Pathology of Brain Aging and Dementia,” appeared online Dec. 19, 2022, in the journal Alzheimer’s disease and dementia. Along with Finch and Thorwald, co-authors are Justine Silva and Elizabeth Head of the University of California, Irvine.
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Original research: Open access.
“The future of amyloid in the emerging pathology of brain aging and dementia” by Max A. Thorwald et al. Alzheimer’s disease and dementia
The future of amyloid in the emerging pathology of brain aging and dementia
Positron emission tomography (PET) studies of patients with Alzheimer’s disease (AD) show a progressive increase in fibrillar Aβ-amyloid. Because current PET ligands underestimate nonfibrillar forms, we tested 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 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 mid- and late-stage AD (Braak 2-3 and 4-6).
Clinical grade AD showed a greater increase in soluble Aβ40 than Aβ42 in CTL. Raft LR yield per gram of AD frontal cortex was 20% lower than control, while cerebellar LR did not differ by Braak score. The extensive overlap of soluble Aβ levels in controls with AD contrasts with the PET findings of fibrillar Aβ.
These findings further support fibrillar Aβ as a biomarker for the treatment of AD and demonstrate the need for more detailed postmortem analysis of various soluble and insoluble Aβ aggregates in relation to PET.
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