Research is often like a game of murder mystery or cluedo; a range of prime suspects with different weapons at different locations
While billions have now been spent on researching dementia in its various forms, progress is still limited and the underlying triggers are still not clear. The majority of research over the past 30 years has revolved around targeting the amyloid plaques that build up in the disease, but this has resulted in limited success. Is it time to focus resources on other hypotheses instead?
The real problem with tackling these conditions is the sheer complexity of the brain and biology. Research is usually a trial and error process filled with intelligent guesswork, but this means it can often take a great deal of time to establish what's actually going wrong. The cause or effect conundrum is a significant roadblock in research and working out which aspects drive a disease and which are a result of another malfunction can take serious resources and time. When researchers first began analysing Alzheimer's patients, perhaps the most obvious feature was the now famous amyloid plaque, but while amyloid may seem like a clear culprit because it's so clearly out of place, it could easily be a smokescreen; the reason why it appears at all may be far more relevant than the plaque itself.
'It's not that amyloid has no role in Alzheimer's. It's clearly a culprit in genetic forms of the disease, and is present in the brains of the majority of patients with non-familial, or sporadic, forms. But that doesn't mean it's causative in all cases'
Neurodegenerative disease generally takes a long time to develop, so it's difficult to model and study accurately. It might be that there is one, or even multiple collaborating factors that lead to Alzheimer's but at this point we still don't know. A consistently effective treatment has not emerged via the amyloid route, but some drugs like solanezumab show some promise if the disease is in its earlier stages. While the amyloid theory isn't yet a dead end, we desperately need a significant breakthrough if we're going to do more than simply delay disease progression.
"Before you abandon your theory, you should turn over every stone. But you have to ask yourself, when do you say uncle?"
About a fifth of patients with Alzheimer's biomarkers don't actually have any evidence of amyloid and about a quarter of those with amyloid don't display any negative symptoms; suggesting either there are multiple forms of the disease or we're still missing a large part of the puzzle. So if the amyloid warpath isn't working too well, what else could it be?
'Researchers are starting to turn over other stones -- and there are many, at different stages of development. These include tau phosphorylation and accumulation, lipid metabolism, neuroinflammation, calcium homeostasis, autophage response, and mitochondrial cascade'
While years of hard work and vast sums of money may be invested in the amyloid hypothesis, the core goal is still to eradicate Alzheimer's disease altogether. Amyloid is certainly a player in many patients, but we can't afford to place all our eggs in one basket when there's so much suffering at stake. If there's a good chance we're wrong, then perhaps it's time to spread out resources and figure out new routes of attack.
"There's no question that 'amyloid' is part of the Alzheimer's story, what is in question, or what should be questioned, is where does it come into the picture? When and how does it affect the clinical features of the disease? Is it a necessary and sufficient factor of the disease process -- i.e. clinical expression -- or merely a co-factor among many other biological processes?"
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