Paracelsus' poison

Paracelsus' poison

New (very distant) Hope For Treating Alzheimer’s?

The recent announcement that Alzheimer’s disease may develop up to 20 years before we can diagnose it by conventional means comes as a coda to a year of turmoil in Alzheimer’s drug development.

The drug company AstraZenica recently announced that they were going to start pushing to develop novel anti-Alzheimer’s drugs. Coming the day after I participated in a media briefing on the recent failures in Alzheimer’s drug development (hey, according to the ABC I’m a leader in Australian Alzheimer’s research, so it must be true. Take note NH&MRC) and the massive disinvestment of drug companies in drug development for the central nervous system (AstraZenica in particular had just decimated its CNS drug development) this was quite a surprise, with a hint of irony.

However, this is an opportunity to give people an insight into how drugs are developed, And why things are rarely smooth. Drug development for Alzheimer’s disease in particular has been very frustrating with a number of high profile drugs that had been slowly moving through the drug registration process having failed, in at least one case quite spectacularly. In the face of this stream of failure, many people are thinking we need to completely rethink what we know about how Alzheimer’s disease (AD) comes about.

AD is just one of many dementias that affect people as they age, but it is the most common one in Australia and most of the developed world. AD incidence increases sharply with age, around 1 in 4 people over 85 years old will be affected by the disease. While most people are aware that AD is associated with increasing memory loss, which is distressing enough in itself, fewer are aware that AD is now the third biggest killer of people over 65. The handful of drugs that we have for AD simply slow the progression of the disease and don’t treat its causes.

In someone with AD, the brain shrivels, however this is the end stage of a much longer process. Until recently, the only way to really determine if someone is suffering from AD or one of the other dementias was to scoop their brain out, slice it up and look for some key pathological hallmarks (not surprisingly most elderly people object to this).

Aside from brain shrinkage there are tell-tale accumulations of protein, dead and dying nerve cells and inflammatory cells called amyloid plaques. With special stains we can also see abnormal tangles of protein inside the nerves.

beta amyloid protein with a fibril disrupting compound bound to it. Ian Musgrave

The protein that forms the plaques, beta amyloid (Aß), is thought to be a key player in AD. Your body makes Aß as a normal part of your brain function. However, normally this protein remains soluble and is cleared from the body. For reasons that are not clear, in AD the Aß folds into a different shape which makes it start to link up with other Aß proteins to make huge insoluble aggregates.

These aggregates (or the clumps of protein leading to the aggregates) are directly toxic to nerve cells (a large part of my research involves squirting aggregated Aß onto pretend nerve cells then trying to stop them dying). They also stimulate the special inflammatory cells in the brain to secrete a range of substances as if they were responding to invading bacteria. But with no bacteria about nerve cells are collateral damage.

We know that in people who have mutations in the Aß protein, or the enzymes which make it, are more likely to develop Alzheimer’s, we know that people who have more copies of the Ab genes are more likely to develop Alzheimer’s. We know that people who have a variant lipoprotein that is not as efficient at clearing Aß are more likely to develop AD. Dogs, who have a similar Aß protein to us, develop an Alzheimer’s like disease while rats and mice whose Aß is different from ours don’t.

When we put the mutant human genes for Aß and its processing enzymes that are associated with high risk for Alzheimer’s into mice, they develop plaques and a number of features (but not all), of the human disease. All this is consistent with Aß being a key player, and a potential drug target.

So drug development has focused on inhibiting the enzymes that make Aß and finding ways to clear Aß from the body, the lead compound for clearing Aß being antibodies.

And they have all been abject failures. More than failure, one of the drugs that inhibited the formation of Aß made people worse. Some people picking over the smoking remains of one of the antibody trials think that there are faint indications that something good might be happening, but scepticism abounds.

How could this have gone so wrong? Biology is complicated, especially the central nervous system, with a huge number of cell types and hormones and neurotransmitters all with multiple and subtle interactions, and the potential for things to pear-shaped is quite high. Even in (comparatively) simpler systems things we think we understand can do as they dashed well please (as a cancer researcher about angiogenesis inhibitors some time).

With such a series of high profile failures, people are suggesting that we need to completely revamp our understanding of the causes of AD and dump Aß as a central player. Even being a dedicated Aß researcher, I’m sympathetic to this idea, but the fact is everything we have tried in AD has failed miserably.

Since 1998 there have been 101 drug trials for AD which have attacked every conceivable mechanism we think is at work in AD. This has resulted in only 3 new drugs, which are variants of the existing disease slowing drugs and don’t attack the underlying cause at all.

Since you won’t get much change from a billion dollars for each drug that makes it into large scale clinical trials, these failures represents a massive hemorrhage of funds from the companies trying to develop anti-AD drugs.

Even when we target other processes we know are involved in AD, such as inflammation and oxidative stress, we have had no success. That goes for Ginkgo and fish oils as well. Given this all pervasive failure of everything, something else must be going on.

And that thing may be time.

This is where the new research comes in. Using a range of sensitive tests for brain function, and detecting the rogue Aß protein in blood and cerebrospinal fluid in people who have a mutation in the Aß gene that makes them more susceptible to AD, the researchers were able to find increases in Aß, changes in brain structure and subtle reduction in brain function up to 20 years before most of these people were due to develop detectable disease.

If the same finding holds true for the vast majority of AD sufferers who do not have this mutation, damage may begin as early as 20 years before we see the frank disease. Our current attempts to treat AD may be far too late to help. By the time we get to diagnosing AD or even the milder forms of memory loss that precede AD, there will have been substantial but subtle damage to the nerve cells.

Right now there is a big trial about to start using a variety of preventative drugs in people with the mutation when they are young, to see if AD can be stopped this way. We will have to wait several years for the results, but we may finally be making inroads into this distressing disease.