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Loss of Peptide Not Amyloid Plaques a New Alzheimer’s Target

It may be that the loss of unaggregated amyloid beta is a cause of Alzheimer's.

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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 [1]. 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.

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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.

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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.

Abstract

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 [18] F-florbetaben or 1.11 for [18]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.

Conclusion

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. 

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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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Literature

[1] 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.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.