A newly identified compound, 2-PMAP, has been found to reduce levels of Alzheimer's-associated amyloid proteins by more than half in animal studies. Researchers hope that this could be developed into a safe preventive treatment for humans.
Five million Americans are currently affected by Alzheimer's disease, which is the most common form of dementia. This number is expected to triple by 2050, unless effective treatments or preventive drugs are developed.
Decades before symptoms of Alzheimer's disease appear in patients, the foundations of the condition are lain by clumps of the amyloid-beta protein accumulating in the brain. As such, amyloid-beta is a prime target for Alzheimer's prevention.
In 2012, a study found that 0.5% of people in Iceland carry a mutation that allows the brain to clear amyloid-beta itself, approximately halving the production of the protein throughout life. People carrying this mutation were found to have a slower cognitive decline and live longer than Icelanders lacking the mutation, and they are fortunate enough to almost never develop Alzheimer's.
Therefore, scientists think that a treatment that mimics this mutation, where amyloid-beta production is lowered in late middle age, would help remove the burden from the brain's natural clearance mechanisms.
Increasingly, research is turning its attention toward preventive methods such as this, rather than treatments to stop Alzheimer's after it has begun.
Preventive treatments are 'the way forward for Alzheimer's drugs'
In clinical trials, every prospective Alzheimer's drug attempting to tackle the disease after it has begun has failed, because brain damage is already severe by the time that symptoms are reported.
Every prospective Alzheimer's drug attempting to tackle the disease after it has begun has failed in clinical trials.
Dr. Martin J. Sadowski, associate professor of neurology, psychiatry, and biochemistry and molecular pharmacology, and lead author on the new study - which is published in the journal Annals of Neurology - says "the key is to prevent the disease process from going that far."
Screening a library of compounds, Dr. Sadowski's team found that even low concentrations of the 2-PMAP compound reduced the production of amyloid precursor protein (APP) - amyloid-beta's "mother protein" - in test cells by more than half.
Transferring this experiment to an animal model, the researchers found that 2-PMAP also had the same effect on APP in the brains of mice engineered to have Alzheimer's-like amyloid deposits.
Levels of APP and amyloid-beta were lowered in the brains of the mice after 5 days of treatment. After 4 months of treatment, levels of amyloid-beta were sharply reduced and prevented the cognitive problems typically observed in mice bred to overproduce APP.
Advantages of 2-PMAP over other Alzheimer's preventives
An advantage of 2-PMAP over other amyloid-lowering compounds is that it can cross efficiently from bloodstream to brain, without any complex modifications. The compound seems to work by interfering with the translation of the APP gene transcript into the protein.
The researchers also believe that 2-PMAP is safer than other compounds that have been tested to lower amyloid-beta. It is effective at low, non-toxic concentrations, so it could potentially be taken daily over many years.
Other potential Alzheimer's preventives work by "cleaving" amyloid-beta from APP, but this function is imprecise - its side effects include a higher incidence of skin cancer and it may even worsen dementia in some cases.
"What we want in an Alzheimer's preventive is a drug that modestly lowers amyloid-beta and is also safe for long term use," says Dr. Sadowski.
The team's next step is to make chemical modifications to 2-PMAP that will improve its effectiveness.
In April, Medical News Today reported on research into Alzheimer's prevention that used a class of compounds called "pharmacologic chaperones" to steer APP away from the part of the cell where it splits into amyloid-beta.
Written by David McNamee