“Alzheimer’s disease may result from slow clearance of amyloid protein in brain,” reported The Guardian.
The research behind this news took 12 people with mild Alzheimer’s disease and 12 people with no dementia and compared the way their brains produced and cleared a protein called amyloid beta. Amyloid beta is normally released in the brain and cleared, but in Alzheimer’s disease the protein accumulates in the brain and causes cell death.
There has previously been speculation that an imbalance of amyloid production and clearance causes Alzheimer’s disease. However, in this study people with Alzheimer’s disease were found to clear the protein 30% slower than unaffected individuals. This suggests that slower clearance of the protein, rather than overproduction, may be a potential reason for the accumulation of protein in the brain in Alzheimer’s disease.
As the researchers point out, this was a small study that cannot say whether impaired amyloid beta clearance is a cause or consequence of Alzheimer’s disease. However, this is exciting research that highlights the importance of amyloid beta clearance in Alzheimer’s disease and provides clear targets for future research.
Where did the story come from?
The study was carried out by researchers from Washington University, and was funded by The US National Institutes of Health, and grants from the Eli Lilly pharmaceutical company, The Knight Initiative for Alzheimer Research, the James and Elizabeth McDonnell Fund, and an Anonymous Foundation charitable organisation.
The study was published in the peer-reviewed scientific journal, Science.
This research was covered well by the newspapers.
What kind of research was this?
This research measured how well people with Alzheimer’s disease could clear a protein called amyloid beta from their brains. Amyloid beta is released by cells in the brain and any excess protein is cleared from the brain. However, in Alzheimer’s disease amyloid beta accumulates and causes brain cells to die. The accumulation of amyloid beta is thought to be caused by an imbalance in the rate it is produced and the rate it is cleared. This research aimed to test whether there was a difference in the rate that the protein was cleared in individuals with Alzheimer’s disease and in people without dementia.
What did the research involve?
The concept behind this research was to use a chemically-tagged amino acid (the building blocks of proteins) to understand how quickly amyloid beta was produced and cleared in the brains of people with Alzheimer’s.
The study recruited 12 people who had mild and very mild Alzheimer’s disease, plus a comparison group of people without dementia. All participants were over 60 years old with no current infections or histories of stroke or blood clotting problems.
The participants received an intravenous infusion of a solution of an amino acid called leucine, which contained an isotope. An isotope is an atom that contains a different number of neutrons but the same number of protons (particles found in the centre of an atom) as other atoms of the same element. The isotope used in this research was 13C6, a relatively rare form of carbon atom that has 13 neutrons rather than just the 12 seen in the majority of carbon atoms.
Leucine is one of the amino acids that make up amyloid beta. The researchers predicted that the participants would make amyloid beta using the 13C6-leucine, thereby allowing them to gauge the speed of production and clearance by monitoring the presence of amyloid beta containing the carbon isotope. To do this, the researchers could collect amyloid beta from the cerebral spinal fluid and measure the amount of 13C6-leucine to observe the rate of its clearance from the brain.
The participants were given the infusion of 13C6-leucine for nine hours, then spinal fluid was taken for up to 36 hours after the start of the infusion. The researchers then determined the rate of amyloid beta production between 5 and 14 hours, and the rate of amyloid clearance between 24 hours and 36 hours.
What were the basic results?
The researchers found that the rate of amyloid beta production did not differ between the people with Alzheimer’s disease and those without. However, the average clearance rate of two forms of amyloid beta, called Aβ40 and Aβ42, was slower in the people with Alzheimer’s disease than in unaffected control subjects. The people with Alzheimer’s disease cleared 5.2 to 5.3% of amyloid beta per hour, whereas the control group cleared between 7 to 7.6% of amyloid beta (p=0.03).
How did the researchers interpret the results?
The researchers said that the method they used to measure amyloid beta production and clearance has been used to measure the effects of drugs that target amyloid beta generation, i.e. looking for decreases in its production.
The researchers say that late-onset Alzheimer’s disease (which affects elderly people rather than the rarer early-onset form that may affect people in their fifties) “is associated with a 30% impairment in the clearance of Aβ40 and Aβ42, indicating that amyloid beta clearance mechanisms may be critically important in the development of Alzheimer’s disease”. Based on this 30% slower rate of amyloid beta clearance, they further estimate that amyloid beta in the brain accumulates over approximately 10 years in Alzheimer’s disease.
This useful research further highlighted the importance of impaired clearance of amyloid beta from the brain as a factor that may contribute to the development of Alzheimer’s disease.
However, as the researchers point out, a limitation of this study was that there were relatively small numbers of people studied (12 in each group), which increases the likelihood of the findings being down to chance. They also say that this research cannot show whether impaired amyloid beta clearance causes Alzheimer’s disease or whether impaired clearance is a consequence of changes to the brain or blood vessels that accompany the disease. In order to establish whether this is a causative factor or not, the researchers would have to follow a far larger group of people over time and from before they had Alzheimer’s disease.
Although preliminary in nature, this research warrants further follow-up to understand possible causes and consequences of poor clearance of amyloid beta from the brain in Alzheimer’s disease.