October 4, 2022

expert reaction to study looking at soluble amyloid-beta (rather than amyloid plaques) and cognition in a group of people with Alzheimer’s disease-causing mutations

A study published in the Journal of Alzheimer’s Disease looks at soluble amyloid-beta, amyloid plaques, and cognition in people with Alzheimer’s mutations.

Dr Karen Marshall, Research Fellow in the School of Life Sciences, University of Sussex, said:

“It has been known for a long time that amyloid plaque burden does not always correlate with cognitive decline in Alzheimer’s Disease.  The observations in this study reporting that high levels of soluble amyloid beta 42 proteins are associated with reduced risk of cognitive impairment are certainly of interest.  Replication of this data would be required to confirm the results, and more lab-based mechanistic studies to explain the hypothesis and discriminate cause from correlation.

“While the data is intriguing, it is becoming ever clearer that Alzheimer’s Disease is a highly complex disease, so it is important to consider all aspects.  This includes the effects of amyloid and in particular smaller oligomers rather than plaques, which feature in a whole host of other diseases and have clearly been shown to have toxic properties.”

Dr Rosa Sancho, Head of Research, Alzheimer’s Research UK, said:

“The risk of developing Alzheimer’s disease is an interwoven mix of genetics, age and lifestyle.  Researchers are unpicking this, and these findings suggest that in even those at greatest genetic risk of Alzheimer’s, research can turn the tide against the disease.

“This study uses existing data from an established group of volunteers who are at a genetically high risk of developing Alzheimer’s disease.  Researchers found that the presence of high levels of a specific form of amyloid – called soluble Aβ42 – is linked to a reduced risk of memory and thinking problems in this group of people.

“While the study could have collected and analysed more data from the cohort of volunteers, such as the levels of other forms of amyloid that may alter how the protein affects the brain, this research provides new insights that could influence how other scientists search for biomarkers and therapies for Alzheimer’s.

“Future research on soluble Aβ42 will show why higher levels of this protein appear to be linked to lower levels of decline in memory and thinking, and it will be interesting to see how this fits with data from emerging successful clinical trials, such as those testing new drug lecanemab – which seems to increase Aβ42 levels as well as clearing amyloid plaques.

“The amyloid hypothesis has been hugely influential in understanding Alzheimer’s disease, but there are many remaining questions to be answered to translate scientific understanding of amyloid into ways to help people with dementia.  At Alzheimer’s Research UK, we know research can and will answer them.”

Prof Bart De Strooper, Director of the UK Dementia Research Institute, said:

“It is known that people with a genetic mutation that drives early-onset Alzheimer’s disease have higher levels of soluble amyloid beta protein in the brain.  However, cognition is only changed after amyloid plaques start to appear in the brain.  At this point, soluble amyloid beta is sequestered into the plaques.  However, other harmful effects including inflammation in the brain and Tau protein aggregation are caused by the plaque formation, not the lowering of soluble protein levels.

“In conclusion, the observations in this paper are confirmatory but in my opinion the interpretation is wrong, and the press release is overstating the impact of the research.”

Prof Robert Howard, Professor of Old Age Psychiatry, UCL Division of Psychiatry, UCL, said:

“Last week’s breakthrough news that lecanemab, a drug that breaks up plaques of amyloid protein deposited in the brains of patients, could modestly improve early dementia, was important supporting evidence for the “Amyloid hypothesis” of Alzheimer’s.  This latest study suggests that the presence of dissolved (rather than deposited) amyloid in the fluid that bathes the brain might actually protect against developing Alzheimer’s in people who carry high risk genes.

“This is important work from a respected group.  Of course, associations with high soluble amyloid levels are not the same as saying that these high levels are directly protective against dementia.  The data show that while we were correct to believe that amyloid is important in Alzheimer’s, the relationship between different forms of amyloid and the development and progression of dementia is more complicated than we thought.”

‘High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations’ by Andrea Sturchio et al. was published in the Journal of Alzheimer’s Disease at 19:30 UK time on Tuesday 4 October 2022.

DOI: 10.3233/JAD-220808

Declared interests

Dr Rosa Sancho: “No conflicts of interest.”

Prof Bart De Strooper: “Prof Bart De Strooper has no direct conflicts with this publication but has been a consultant for companies that develop anti-amyloid therapies.”

Prof Robert Howard: “No relevant CoIs.”

For all other experts, no reply to our request for DOIs was received.