The tragic state of affairs in Alzheimer’s disease research
The federal government recently set the goal to have a treatment for Alzheimer’s disease (AD) by the year 2025. Given the large amount of resources that are allocated to investigating the disease, it seems a reasonable goal. There is one problem though. Research in the AD field has been stuck in neutral for a very long time and seems now determined to go in reverse, all the way to where it started 20 years ago, when the modern tools of science were first applied to the problem. It would almost be comical if it were not for the tragic consequences, social, emotional and financial, not only to the sufferers and their families, but to society in general, that are associated with this devastating condition.
So why are we heading in the wrong direction? Let us go over the facts. Over two decades ago, researchers found that the Alzheimer’s brain had two distinct pathological features, which they called senile plaques (SPs) and neurofibrillary tangles (NFTs). Both are sticky masses in the brain that are thought to interfere with its function and eventually kill brain cells, causing the symptoms of dementia.
Researchers quickly came up with the amyloid hypothesis to explain how SPs and NFTs might cause damage in the AD brain. The hypothesis is so called because a peptide called amyloid accumulates over time and aggregates into the sticky masses that are the SPs. In a nutshell, this hypothesis states that the amyloid peptide initiates the disease, leading to the formation of NFTs and the death of brain cells. It was thought that, if one were able to remove amyloid from the brain, one would cure the disease. In those early days, there was good genetic and biochemical evidence to support that strategy, and almost every research dollar available ever since has been poured into it. The problem is that, 20 years and billions of dollars later, that strategy has been proven to be a waste of time and resources.
How so? In clinical trials with drugs designed to reduce the amount of amyloid in the brain, patients do indeed show significant decreases in amyloid (meaning that the drug did what it was supposed to do), and yet the patients do not show any improvement; if anything, they deteriorate faster.
If that were not enough to convince people that SPs are not the be-all and end-all of AD, here’s another fact: it turns out that SPs are present in 20-40% of people with no cognitive problems, let alone signs of dementia. So one does not have to be a brain scientist to see that we should not be aiming to cure AD by targeting SPs as the bad guys.
It is much more likely that SPs are the consequence, not the cause, of the condition. Imagine the progression into Alzheimer’s disease as a battle between the brain and stress factors in which amyloid is the brain’s weapon and the stress factors are the enemy that will eventually cause the disease. Amyloid accumulates over time as a consequence of the continuous battle in the brain, eventually aggregating into the sticky masses that are the SPs. In other words, SPs would be the “corpses” in the battlefield after the war against AD. That would easily explain the failure of clinical trials designed to remove amyloid from the brain (because they are effectively depleting the brain’s defenses). It would also explain the presence of SPs in non-demented individuals, in whom the battle against AD took place and “the brain won”.
The above scenario has not been proven, but it does account for the current known facts better than the amyloid hypothesis does. But here’s the problem: the lion’s share of research funds is still allocated to scientists who base their research on the assumption that amyloid is the main cause of Alzheimer’s disease, despite the overwhelming evidence to the contrary. These are the most influential scientists, the ones who currently make the key decisions about what research gets published and funded. Perhaps they are too invested intellectually and/or financially in the outcome of research and clinical trials based on amyloid biology. Whatever the reason, the current situation is not acceptable; we need to give breaks to scientists who come up with reasonable alternative ideas to study AD. This is not happening.
Instead of taking a few steps back and making funding decisions based on objective evidence, it seems as if the leading scientists are doubling down on the amyloid hypothesis. That is bad science and it will bring devastating consequences, as Alzheimer’s disease slowly but surely turns into the biggest medical problem of our time.