Does a specific form of amyloid protect us from memory and thinking problems?

Research in the US published today (Tuesday 4 October) suggests that the presence of high levels of a form of the amyloid protein – soluble Aβ42 – in the brain could reduce the risk of memory and thinking problems in people who have high genetic risk of developing Alzheimer’s disease.

What did the researchers do?

A characteristic sign of Alzheimer’s disease is the build-up of amyloid proteins into aggregates in the brain. Researchers looked specifically at a form of this protein – soluble amyloid-beta 42 (Aβ42).

Previous work has investigated people who are amyloid positive (meaning the results of a specialised scan shows amyloid in their brain) and have a high risk of developing Alzheimer’s, due to having rare genetic mutations, and found those who had have normal memory also had high levels of soluble Aβ42.

The researchers investigated whether having high levels of soluble Aβ42 was better for maintaining normal memory and thinking, compared to having lower levels of amyloid in the brain, as well as lower levels of a protein called tau in their cerebrospinal fluid.

Participants in this study came from the Dominantly Inherited Alzheimer Network (DIAN) and were either amyloid positive or negative, which was confirmed by a PET scan showing amyloid protein in the brain.

In total 232 participants were involved in this study, with 108 being amyloid positive, and they were followed up for around three years. Everyone in the study had brain scan information, as well as memory and thinking test data over the three years.

What did they find?

Results from the study are based on a smaller sample of people as some data was missing.

Amyloid positive people with rare genes that cause Alzheimer’s disease, who also had soluble Aβ42 detectable in the liquid surrounding their brain and spinal cord (known as cerebrospinal fluid, (CSF)), were associated with a reduced risk of memory and thinking problems, as well as less damage and shrinkage to parts of the brain involved in memory.

People with lower levels of soluble Aβ42 appeared to have greater cognitive decline, showed by worse memory and thinking scores in tests.

These results suggest testing people’s CSF for lower levels of soluble Aβ42 could be a better biomarker of Alzheimer’s disease progression than testing for high tau levels or doing specialist brain scans to show amyloid in the brain. Specifically, levels of CSF Aβ42 above 270 pg/ml could be used to predict a reduced risk of memory and thinking problems.

Our expert comment:

Dr Rosa Sancho, Head of Research at 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.”