A recent study, led by the University of Cincinnati in collaboration with the Karolinska Institute in Sweden, challenges the popular amyloid hypothesis that has dominated Alzheimer’s research for decades.
Amyloid accumulation may be the consequence, not the cause
Over 100 years ago, Alois Alzheimer originally identified amyloid-beta plaques in the brains of people with the disease, and since then, a lot of focus has been on targeting those plaques. This has also meant that the greater share of funding has gone into developing drugs that target the plaques rather than exploring other possible avenues of approach.
Going against the established amyloid hypothesis, the researchers suggest that the formation of amyloid plaques is a consequence but not the cause of Alzheimer’s disease.
Results from the Alzheimer’s Disease Neuroimaging Initiative study suggests that the successful treatment of Alzheimer’s disease might not be in targeting amyloid plaques . Instead, normalizing the levels of amyloid-beta peptide, a protein present in the brain, may be the key to combating this disease.
Amyloid-beta peptide is an important protein for brain health while in its soluble form. However, it can begin to misfold and form clumps known as amyloid plaques. The accumulation of amyloids is linked to loss of proteostasis and is believed to be one of the reasons we age.
Testing their new hypothesis
The researchers believe that the cognitive impairment caused by Alzheimer’s could be due to a decline of the soluble amyloid-beta peptide and not the buildup of amyloid-beta.
In order to test this hypothesis, the team analyzed brain scans and spinal fluid samples from 600 participants enrolled in their study. The participants all had amyloid plaques present in their brains.
Using the data from this, they then compared the presence of plaques and levels of soluble amyloid-beta peptide against people with healthy cognitive function. They discovered that regardless of the presence of amyloid plaques, people with high levels of soluble amyloid-beta peptide had normal cognitive function.
In addition, they also reported that there was an association with a high level of soluble amyloid-beta peptide and a larger hippocampus, a part of the brain responsible for memory.
The researchers noted that as we grow older, most people will have some level of amyloid plaques. They suggest that by the age of 85, around 60% of people have some level of amyloid accumulation, and yet only 10% will develop Alzheimer’s.
The next step for the researchers is to test their findings in animal models of Alzheimer’s disease. This will also include testing replenishing soluble amyloid-beta peptide levels in order to restore healthy brain function.
Another approach that could work in combination is to prevent the peptide from clumping and forming plaques in the first place.
Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid β amyloid (Aβ42) peptide levels are associated with normal cognition and hippocampal volume despite increasing brain amyloidosis.
This cross-sectional study of 598 amyloid-positive participants in the Alzheimer’s Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for  F-florbetaben or 1.11 for F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p-tau, t-tau, and centiloids levels.
Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aβ42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p < 0.001) or MCI (1.42; p = 0.006). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume.
The data appears to suggest that the development of Alzheimer’s may be more dependent on the decline of soluble amyloid-beta peptide than the accumulation of amyloid plaques.
As the old saying goes, never put all your eggs in one basket. In biology, there are often multiple possible routes to take to tackle a problem, and we should be open to exploring all of those with scientific merit.
Let us hope that this direction of research yields positive results and breaks the stalemate that amyloid-targeting drugs appear to have reached. Speaking as someone who has watched a close relative develop Alzheimer’s and have their memories and who they were slowly stolen from them, the day we find a cure could not come soon enough!
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 Sturchio, A., Dwivedi, A. K., Young, C. B., Malm, T., Marsili, L., Sharma, J. S., … & Espay, A. J. (2021). High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis. EClinicalMedicine, 100988.
July 16, 2021
Great read! Is there any way to naturally replenish soluble amyloid-beta peptide levels in order to restore healthy brain function?
July 17, 2021
This paper is a step forward towards a better understanding of the importance of preserving Amyloid Beta monomer physiology. Unfortunately the paper does not discriminate between soluble physiological Abeta monomer and soluble toxic Abeta oligomers, which is essential to design the optimal immunotherapy.
Only highly oligomer selective immunotherapies will effectively eliminate the pathology while not interfering with the physiology of soluble native Abeta monomer homeostasis.
For a more detailled discussion:
H.Hillen. The Beta Amyloid Dysfunction Hypothesis for Alzheimer’s Disease. Front. Neuroscience. 2019 Nov 7;13:1154
with best regards
July 17, 2021
I wonder if there is any reasearch of how light might affect alzheimers disease. Like… I mean litterally using light on the brain the same way one would use light on an egg to see the inside. This would create light signals which the protein will probobly react to. Of course different colours, strenght and time would effect how the protein would react. I Might be way off but I just feel like there is an answer. Light, heat, electricity and vibration. Somewhere there should be an answer I think, I just dont know what.
July 18, 2021
As there are currently no really good animal models of Alzheimer’s disease, it would be interesting to try and deplete soluble amyloid-beta peptide in a primate and see what happens.
It would also be good if this approach could be tested quickly in a fruit fly or daphnia model first.
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