This piece in The Guardian 5 days ago is typical of the hype and hoopla that attended the unveiling of solanezumab's apparent positive affect on patients suffering from mild cognitive decline in an Alzheimer's disease study. Despite the fact that the medical scientists running the Eli Lilly trial admitted that the arrest in cognitive decline was so subtle that friends and relatives of any person concerned would not have noticed it, the result, found by recognizing a sub-group of mild decline patients among pooled data that showed no statistical relevance, is being hailed as a breakthrough because all previous trials of solanezumab have proved negative - as have trials of all drugs for Alzheimer's that have been produced to either interfere with the enzymatic chain by which beta amyloid is produced in the brain, or remove beta amyloid from the brain. This excited hype is typified by a quote in the Guardian article: “This is the first evidence of something genuinely modifying the disease process,” said Dr Eric Karran, director of research at Alzheimer’s Research UK. “It’s a breakthrough in my mind. The history of medicine suggests that once you get through that door you can explore further therapeutic opportunities much more aggressively. It makes us less helpless.”
Well, in reality, it falls far short of a breakthrough. The very subtle apparent effect was found by massaging the trial statistics, has not been subjected to peer review in a learned journal, and is yet to be bolstered by a dedicated trial of solanezumab on mild cognitive decline patients. The hoopla ignores several very important points:
1. Its postulated effect is by removing soluble molecules of beta amyloid from the brain, whereas the main postulated toxic form of beta amyloid are oligomers of a number of molecules.
2. A great many people die in their 70s, 80s and later and are found, on autopsy, to have substantial deposits of both beta amyloid plaque and neurofibrillary tangles of tau protein in their brains yet died with pin-sharp cognition for their age.
3. All the drugs, including solanezumab, that have been produced, tested, and found wanting so far have targeted the genes that produce amyloid in people with the familial type of the disease - the type that is passed down generations. Yet this accounts for only 1% of people who eventually develop Alzheimer's.
4. The three big GWAS (genome wide association studies) conducted so far to find subtle associations between genes and disease, on Alzheimer's disease, found no significance for the genes implicated in familial Alzheimer's disease. They simply did not feature.
5. The one gene that will demonstrably greatly increase your risk of contracting Alzheimer's is APOE epsilon 4, which is involved in lipid (fats) metabolism in the brain, not the production or clearance of beta amyloid.
It remains to be seen whether further science backs up these very tenuous results. In the meantime we would be very advised to reach for the salt cellar and remember that beta amyloid is not always the villain - it has, in appropriate concentrations, important roles to play in the brain either fighting pathogens or regulating transmission of nerve impulses across synapses between our billions of neurons. To my mind the balance of evidence so far suggests strongly that Alzheimer's is a disease of neurons rather than amyloid and amyloid may well be simply the rubble left behind after the disease process has taken hold and countless neurons have been destroyed.
Other, sensible commentators have made the point that it may be too much to expect ANY drug to cure Alzheimer's when administered to individuals in whom the disease is already advanced. Too much irreversible damage has been done to their brains. This is why two big trials are presently testing the so-called amyloid hypothesis to destruction by identifying populations of individuals known to be at enlarged risk of early-onset Alzheimer's (perhaps because they harbour significant mutations to one or other of the genes controlling steps in the pathway that produces amyloid) and treating individuals from a young age before any cognitive tests or brain scans reveal deficits to see if they can stave Alzheimer's off.