For more than 40 years, researchers have widely believed that Alzheimer’s disease symptoms are largely due to a buildup of insoluble plaques of beta-amyloid in the brain. This is known as the amyloid cascade hypothesis.
According to this hypothesis, soluble beta-amyloid protein is deposited and forms insoluble amyloid plaques, which damage neurons and synapses.
This impairs the normal transmission of nerve impulses, leading to typical dementia symptoms, such as memory loss, language problems, and unpredictable behavior.
Recent research has questioned this idea. Many people with amyloid plaques have no symptoms of dementia, and treatments aimed at slowing the buildup of plaques have shown little effect on the progress of the disease.
Now, a new study from the University of Cincinnati, OH, which appears in the Journal of Alzheimer’s Disease, suggests an alternative theory — that Alzheimer’s symptoms are caused not by an increase in insoluble amyloid plaques, but by a decrease in the soluble beta-amyloid that is essential for cognitive function.
Amyloid plaques have long been seen as a major cause of Alzheimer’s disease symptoms, and a target for therapies.
However, earlier this year, Dr. Matthew Schrag, assistant professor of neurology and director of the Cerebral Amyloid Angiopathy Clinic at Vanderbilt University alleged that an influential and widely cited 2006 study that led many researchers to study amyloid plaques may have falsified images.
In the current study, researchers built on findings from their previous research that people with high levels of soluble beta-amyloid were cognitively normal, even if they had amyloid plaques.
Those with lower levels of soluble beta-amyloid were more likely to show cognitive impairment.
The researchers hypothesized that it was not the buildup of insoluble amyloid plaques, but the accompanying decrease in soluble beta-amyloid that was causing the symptoms.
The study looked at people participating in the Dominantly Inherited Alzheimer Network (DIAN) cohort study. These people have mutations that make them more likely to develop amyloid plaques in the brain, which is thought to increase their likelihood of developing Alzheimer’s disease.
Dr. Anton Porsteinsson, professor and director of the Alzheimer’s Disease Care, Research and Education Program (AD-CARE) at the University of Rochester Medical Center, who is part of the DIAN consortia, but not an author of the study, told Medical News Today:
“This is a very unique participant group. All have dominantly inherited Alzheimer’s disease which is a decisively small subgroup. They may be different in some ways than the much more common sporadic AD group. The DIAN Cohort Study is very well designed and considered.”
The researchers performed clinical assessments for cognitive function, using the Clinical Dementia Rating scale, on all participants. They also measured [beta-amyloid-42], p-tau, and t-tau levels in their cerebrospinal fluid (CSF), and used neuroimaging to quantify insoluble brain plaques.
The participants were tested at the beginning of the study and after a mean follow-up time of 3.3 years (range of 1-9 years).
Participants with higher levels of soluble beta-amyloid were less likely to show cognitive decline, even if they had amyloid plaques. Lower levels of soluble beta-amyloid were strongly associated with faster cognitive deterioration.
Dr. Porsteinsson commented: “Here, we have DIAN participants that are amyloid PET scan positive so they have elevated amyloid plaque burden. You would expect their soluble CSF and plasma [beta-amyloid-42] to be low as the plaques absorb them from the soluble form.”
“Here,” he added, “those that have higher soluble [beta-amyloid-42] seem to perform better than those that have lower [beta-amyloid-42] in terms of disease stability. Maybe they have milder stage of disease or lower oligomeric amyloid form burden.”
In the study, those with a baseline level of soluble beta-amyloid in the brain above 270 picograms per milliliter remained cognitively normal regardless of the amount of amyloid plaques in their brains.
“What is new here in my book is that soluble [beta-amyloid-42] concentrations and plaque burden don’t go hand in hand and that a drop in soluble [beta-amyloid-42] is a stronger predictor of bad clinical course than plaque burden.”
– Dr. Anton Porsteinsson
Lead author Prof. Alberto Espay commented: “It’s only too logical, if you are detached from the biases that we’ve created for too long, that a neurodegenerative process is caused by something we lose, amyloid-beta, rather than something we gain, amyloid plaques.”
“Degeneration is a process of loss, and what we lose turns out to be much more important,” he added.
The authors are moving on to investigate whether therapies that increase the level of soluble beta-amyloid could be effective in combating Alzheimer’s disease.
“The possibility that higher levels of soluble [beta-amyloid-42] is therapeutic and that promoting soluble [beta-amyloid-42] could be therapeutic is truly intriguing.”
– Dr. Anton Porsteinsson
The researchers suggest that a similar mechanism may operate in Parkinson’s disease. Insoluble deposits in the brain, called Lewy bodies, are thought to cause many of the symptoms.
However, the researchers hypothesize that it may be a decrease in levels of normal, soluble alpha-synuclein, rather than its build-up into insoluble Lewy bodies, that is responsible.
However, some experts noted that the findings from this small sample, all of whom possess a rare gene that predisposes them to Alzheimer’s disease, should be treated with caution.
Dr. Rebecca Edelmayer, Alzheimer’s Association senior director of scientific engagement, told MNT that “[b]eing able to detect and measure brain changes associated with Alzheimer’s and accurately predict progression into cognitive decline is incredibly important both clinically and in research.”
She continued: “This paper’s finding that CSF [beta-amyloid-42] levels can be predictive of brain amyloid levels is already known. However, the conclusion that high levels of CSF [beta-amyloid-42] [are] a better predictor of protection from cognitive decline, even in individuals that already have amyloid plaque, may be an overstatement based on the samples analyzed and does not prove any new hypothesis or refute any standing hypothesis.”
So, although this study opens up new areas for investigation in the hunt for effective therapies, it does not yet provide the magic bullet against Alzheimer’s disease and other neurodegenerative disorders.
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15/10/2022