Poor Plaque protein Elimination is Linked to Alzheimer’s disease

Alzheimer’s disease appears to be caused by the brain’s poor elimination of a plaque component, beta-amyloid protein, rather than simply the accumulation of it, researchers from Washington University School of Medicine, St. Louis revealed in the journal Science. We already knew that beta-amyloid protein accumulation occurs in Alzheimer’s patients; this study reveals something nobody knew – that it is the poor clearance of the protein rather than its accumulation that is at the heart of the problem.

The authors say the brain’s failure to clear away a waste product (beta-amyloid) of normal metabolism fast enough results in a build-up of it, leading to the growth of plaques that can corrupt brain cells and cause Alzheimer’s disease.

Randall Bateman, MD, said:

“Clearance is impaired in Alzheimer’s disease. We compared a group of 12 patients with early Alzheimer’s disease to 12 age-matched and cognitively normal subjects. Both groups produced amyloid-beta (a-beta) at the same average rate, but there’s an average drop of about 30 percent in the clearance rates of the group with Alzheimer’s.”

The researchers have worked out that a decade of poor beta-amyloid clearance would be enough for an accumulation equal to that seen in Alzheimer patients’ brains.

The authors say their findings will have major implications for Alzheimer treatment and diagnosis.

Scientists will now want to find out how beta-amyloid, also known as a-beta, a byproduct of normal metabolism, is expelled from the brain, broken down, and got rid of by the body. The more they find out about this, the better doctors will become at diagnosing Alzheimer’s before symptoms appear. Pharmaceutical companies might also be able to develop medications one day that restore effective a-beta clearance from the brain before Alzheimer’s symptoms appear, hopefully preventing the disease.

We have long known that a-beta plays a vital role in the formation of brain plaques that are found during autopsies of people with Alzheimer’s disease.
Experts say that the brain expels a-beta, which is produced by brain cell activity, by moving it to the spinal fluid, from where it is disposed. Some previous studies had suggested that low a-beta levels in the spinal fluid might possibly be an indicator of Alzheimer’s disease before symptoms appear, perhaps because a-beta is still stuck in the brain and building up there.

The results of this study will lay to rest some experts’ doubts about whether a-beta might not be causatively linked to Alzheimer’s.

Bateman said:

“These findings support the idea that impaired a-beta clearance is fundamentally linked to Alzheimer’s disease.”

In this study, the researchers used SILK (stable isotope-linked kinetics), a process they developed themselves. SILK allows them to measure a-beta clearance rates, as well as production rates. The patients were given an intravenous drip the amino acid leucine that had been very slightly altered to label it.

The labeled leucine is picked up by the brain and incorporated into the new copies of a-beta proteins, as well as some others. Over a period of a few hours, periodic samples of the patients’ cerebrospinal fluid were taken through a lumbar catheter. They purified the a-beta from the samples and could determine how much of it included labeled leucine. The scientists were eventually able to measure the individual’s a-beta production rate.

As soon as the percentage of a-beta containing labeled leucine peaked, the scientists stopped introducing the labeled laucine and took periodic samples of the participants cerebrospinal fluid. This way they could measure how quickly their nervous systems eliminated the labeled a-beta. In other words, they could work out the how good the brain was at clearing out a-beta.

The study involved 24 subjects; 12 healthy individuals and 12 with early Alzheimer’s.

There was a considerable difference between the a-beta clearance rates of the Early Alzheimer’s Group and the Healthy Group. However, some participants in the Healthy Group had clearance rates very close to those in the Alzheimer’s Group. The question now is – are these seemingly healthy patients developing Alzheimer’s before symptoms begin to appear...?