September 14, 2021

expert reaction to study on liver protein a-beta and Alzheimer’s

Research, published in PLOS Biology, has looked at liver protein a-beta and Alzheimer’s.

Prof Tara Spires-Jones, UK Dementia Research Institute Programme Lead and Deputy Director, Centre for Discovery Brain Sciences, University of Edinburgh, said:

“This paper from Prof Mamo and team provides data showing that in mice, expressing an Alzheimer’s related gene in liver causes brain changes.  While these data are interesting, the mice do not show typical Alzheimer’s disease related brain changes like clumps of tau and there was not a thorough characterization of brain cell death.  This study in small groups of mice is interesting but there is a long way to go to understand whether liver proteins might contribute to human Alzheimer’s disease.”

Dr Axel Montagne, Group Leader at the UK Dementia Research Institute, University of Edinburgh, said:

“This study provides compelling evidence that amyloid produced in the liver may contribute to the development and progression of Alzheimer’s brain pathology. It’s an exciting result and adds to the growing literature that the origins, or at least drivers, of some neurodegenerative diseases may lie outside of the brain. 

“Interestingly, in this new animal model produced by the researchers, significant problems develop at the blood vessels interfacing the brain and the rest of the body – the blood brain barrier. It is difficult for many drugs to access the brain so targeting the blood brain barrier directly or amyloid in the liver, could offer a very attractive treatment option at the earliest stages of disease. 

“However, the idea that Alzheimer’s may begin in the liver is not completely new. A decade ago, a group from California¹ used a drug to reduce levels of amyloid outside of the brain – Gleevec, which is used to treat leukaemia, because it cannot cross the blood brain barrier. They saw that administering Gleevec into the bloodstream for a week reduced the amount of amyloid in the brain by half, even though the drug cannot get gain access. This suggests that a considerable amount of amyloid found in the brain originated from the rest of the body. 

“Aerobic exercise, healthy diet, no smoking, and limited alcohol consumption are known to be the most important lifestyle factors that can keep your liver, blood brain barrier and brain healthy. So adopting this healthy lifestyle is likely to keep hepatic, cardiovascular, and brain functions sharper over a longer period of time.

“Additionally on diet – docosahexaenoic acid (DHA), an omega-3 fatty acid derived from diet or synthesized in the liver, is known to decrease the risk of developing Alzheimer’s disease. So eating foods high in DHA such as seafood (e.g., mussels, oysters, clams, crabs) and oily fish (e.g., salmon, trout, tuna, anchovies) is one way to keep your brain healthy too. Your body can only make a small amount of DHA from other fatty acids, so you need to consume it directly from food or a supplement.”

¹ Sutcliffe JG, Hedlund PB, Thomas EA, Bloom FE, Hilbush BS. Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: implications for Alzheimer’s disease. J Neurosci Res. 2011 Jun;89(6):808-14. doi: 10.1002/jnr.22603. Epub 2011 Mar 3. PMID: 21374699.

Dr Susan Kohlhaas, Director of Research at Alzheimer’s Research UK, said:

“The brain doesn’t operate in isolation from the rest of the body and there is growing evidence to suggest that other organs can have important effects on our brain health. In this well-conducted early-stage experiment in mice, researchers demonstrated that amyloid produced only in liver cells can lead to Alzheimer’s-like processes in mice.

“There are good reasons to think that the amyloid protein that builds up in the brains of people with Alzheimer’s is produced by brain cells, but over the years researchers have suggested that other sources of amyloid may play a role in the disease.

“If liver cells were found to produce amyloid that contributes to Alzheimer’s in people, this may open new avenues for lifestyle changes and drugs to limit amyloid production, but we will need to see much more evidence before we can know whether these approaches would be worth pursuing.

“As with any research carried out in mice, we will need to explore how relevant these findings are to Alzheimer’s disease in people. Continued investment into research is the only way to follow up on findings like these and investigate how we can best overcome diseases that cause dementia.”

Prof David Curtis, Honorary Professor, UCL Genetics Institute, said:

“This interesting study suggests that the damage to the brain which occurs in Alzheimer’s disease may be due not only to A-beta protein produced inside the brain but also to A-beta which is produced in other organs and which is carried to the brain in the bloodstream. This suggests that lowering blood levels of A-beta might be an effective way to prevent Alzheimer’s disease progressing. This is important because it is in general much easier to produce effective treatments targeting substances in the blood than in the brain – indeed many drugs cannot enter the brain because of a membrane called the blood-brain barrier. It also means that one might be able to monitor the effectiveness of treatments simply by measuring A-beta levels in the blood, which again is much easier than trying to work out what is happening within the brain. Overall, this work could give a substantial boost to efforts to develop effective treatments for this terrible disease.

“I’m afraid I don’t really agree with the author’s suggestion that reducing lipid levels in the blood, for example by making changes to diet, could reduce A-beta and reduce the risk of Alzheimer’s disease. I think if there was a strong connection between lipid levels and Alzheimer’s disease risk then we would already know about it from previous studies. Though obviously it’s important to pursue a healthy lifestyle for other reasons. I think the main value of this research will be to make it easier to develop new effective treatments for Alzheimer’s disease which target the A-beta levels directly.”

‘Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype’ by V Lam et al. was published in PLOS Biology at 7pm UK time on Tuesday 14 September 2021.

https://doi.org/10.1371/journal.pbio.3001358

Declared interests

Prof Spires-Jones: I have no conflicts of interest with this study.

Dr Axel Montagne declares that he has no conflicts of interest

Prof Curtis: I have no conflict of interest to declare.

Dr Kohlhaas: No conflicts.