A drug has been shown effective in clearing away toxic proteins in human brains thought to cause Alzheimer’s disease, a new study shows.
But, researchers warn, there’s more work needed before the drug, called aducanumab, moves into the clinic – if it ever does.
The work, published in Nature, is “tantalising, but not definitive”, says University College London neuroscientist John Hardy.
Alzheimer’s disease is a common neurodegenerative disorder among older folk. One in nine people over the age of 65 years has the disease.
Outwardly, symptoms include memory loss, confusion, dementia and mood changes. But the changes that occur within the brain are much sneakier, often accumulating for decades before any cognitive or emotional symptoms emerge.
One of the main culprits is beta amyloid protein. Everyone has a little beta amyloid in their brain, but in Alzheimer’s disease it amasses as insoluble clumps – particularly in the hippocampus, the brain structure responsible for learning and memory.
Cells surrounding these clumps shrink and die.
But treatment isn’t as easy as scooping out the plaques. The brain’s first line of defence is the blood-brain barrier – a network of tightly packed cells that line blood vessels.
So the challenge has been to find a drug that can pierce the blood-brain barrier, hunt down amyloid clumps and dismantle them for the brain’s own immune cells, called microglia, to dispose of.
A recent promising candidate was aducanumab. It can breach the blood-brain barrier and it selectively binds to amyloid aggregates – can it help clear them away too?
Boston-based pharmaceutical company Biogen and scientists from the US and Switzerland administered aducanumab to mice genetically engineered to over-produce amyloid. They found the drug bound to and shrank amyloid clumps in the mouse brain.
It was a good start. But mice and humans, while similar in many ways, are very different in others. Could it work in people too – and could the dose affect how well it performed?
The team recruited 165 patients diagnosed with mild Alzheimer’s disease and randomly allocated them to one of four groups: a placebo group or one of three treatment groups that would receive monthly intravenous aducanumab for a year.
The first treatment group was injected with three milligrams of aducanumab per kilogram of weight, the second received six milligrams per kilogram and the final, 10 milligrams per kilogram.
Before beginning treatment (or placebo – patients weren’t told which group they were in) their brain was scanned using a technique called florbetapir PET, which detects brain amyloid levels.
As expected, all brains contained high levels of beta amyloid. After a year of treatment or placebo, they were scanned again.
Those taking the placebo saw no change in brain amyloid levels. (No less, but no more either. This suggests the participants reached amyloid brain saturation before the trial began.)
The aducanumab groups, though, had much of their amyloid cleared away. The effect was dose-dependent too, with those on the highest dose receiving the most benefits.
While this all sounds fantastic, the team admits the work has a number of limitations.
The initial cohort of 165 – which was from the US only – was whittled down to 125 over the course of the year. Some 20 participants experienced side effects such as headaches and dropped out.
The researchers didn’t measure, to a great extent, how well the patients did cognitively after treatment either.
A couple of tests showed a trend of slowing cognitive decline in the aducanumab-taking patients, but it was not definitive.
“The good news is that by scanning patient brains the researchers show the drug is doing its job in reducing amyloid beta levels within the brain,” says Mark Dallas, a neuroscientist at the University of Reading in the UK.
“However, because of the study design, it cannot tell us if there is any improvement in brain function of those that received the drug.”
And while aducanumab targets beta amyloid, it ignores another aspect of Alzheimer’s pathology, tau aggregates.
Tau proteins, which form part of a cell’s interior transport system, warp with the disease. These tau tangles disrupt a cell’s functioning and it eventually dies.
Still, more clinical trials will elucidate aducanumab’s cognitive effects. It might be that clearing amyloid is enough to give patients a few more years of clear thinking.
Indeed, the researchers write, phase 3 testing is in development. Statistically, the odds are stacked against them – only 0.4% of Alzheimer’s drugs make it past phase 3 trials. Only time will tell.
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