A recent paper published in Nature, and widely reported in the general press, has got people talking about the possibility of curing Alzheimer’s disease. While discoveries such as this are exciting, just how much importance should we be attaching to them? By reporting them as “game-changing breakthroughs”, are we guilty of encouraging naïve optimism for an imminent cure?
Here we will take a look at the disease and the various theories on routes by which it arises, as well as how Sevigny et al’s recent findings could potentially be translated into a treatment to benefit sufferers in the future.
Alzheimer’s disease for the sufferer: symptoms and diagnosis
Alzheimer’s disease is the most prevalent form of dementia and affects over half a million people in the UK, accounting for over 60% of all dementia cases. Although the most well-known symptom is memory loss, Alzheimer’s is different for each sufferer. Other symptoms include mood and personality changes, confusion about timelines and locations and ability to perform daily tasks can be impaired.
These and the many other symptoms are hugely distressing for the sufferer but also for their families and friends, who in many cases become their carers. Shockingly, the Alzheimer’s Society estimates that over a billion hours were spent caring for dementia sufferers in 2013. As the number of sufferers rises each year, so does the burden on carers and the need to find more effective treatments.
Alzheimer’s is usually diagnosed by a series of tests and questions, in the form of the mini mental state examination (MMSE) or the clinical dementia rating (CDR). These assign scores to patients’ answers to memory, attention and language tests, and more. Alongside these tests, there are often physical examinations and brain scans to corroborate the presence of the tell-tale symptoms of Alzheimer’s.
Why does Alzheimer’s happen?
Despite the prevalence of Alzheimer’s, there is still a long way to go before it is properly understood and a potential cure, or successful treatments, are found. Although huge amounts of research being undertaken to try and achieve this goal, Alzheimer’s is proving an elusive beast with multiple potential causes.
One theory, now widely accepted to be flawed, and yet upon which most currently available Alzheimer’s drugs are based, is the “cholinergic” hypothesis: that Alzheimer’s is caused by a reduction in the production of an essential chemical for correct brain function: acetylcholine.
Cancer vs Dementia
Yet another theory suggests that Alzheimer’s is caused by imbalances in the energy processes occurring inside neurons and other related cells in the brain, leading to overuse of some cells and death of entire areas of neurons. This has been termed the “inverse Warburg effect” and has been associated with the surprising fact that many cancer sufferers do not get dementia, and vice-versa, as both diseases can be explained by changes to metabolic processes within cells. This could open up a new avenue to treatment development, concentrating on cell metabolism rather than faulty genes (it seems that many disparate genes may play a role in Alzheimer’s) and the build-up of damaging protein agglomerates in the brain, which is currently the most popular school of thought as to the cause of Alzheimer’s. This is the so-called “amyloid hypothesis”.
When genetics hinders brain function
The amyloid hypothesis is based on the idea that various factors, predominantly age, but also genetics (including the presence of a gene which means the brain is less able to break down deposits as they form) lead to the accumulation of misfolded proteins known as amyloid-beta (Aβ) in the brain, which form amyloid fibrils and plaques, causing damage or death to neurons and giving rise to the symptoms of Alzheimer’s.
Alongside this there may be accumulation of another protein referred to as tau, which also forms aggregates and tangles which lead to neuron damage, and eventual loss.
Numerous studies have concentrated on the amyloid hypothesis to try and develop therapies to halt this cascade at some point and hence slow, or stop, the brain’s decline. The most recently publicised findings, which have got the press and public so excited, take this hypothesis as their starting point.
Sevigny et al’s research findings: immunotherapy to remove damaging proteins
These findings, which have caused such excitement in the press and among the general public, come from a paper by Sevigny et al. It concentrates on the effectiveness of a specific immunotherapy on reducing Aβ plaques in Alzheimer’s patients who were all sufferers of mild or pre-symptomatic Alzheimer’s. The immunotherapy uses antibodies which attack the Aβ plaques, and which also enlist the help of some of the brain’s own immune cells to clear the fibrils. Some of the images from the study are indeed very exciting in terms of the reduction in Aβ plaque presence:
Despite these interesting findings, the study was actually intended to just assess the safety and tolerability of the aducanumab, and the paper itself cautions against interpreting the cognitive results too favourably. However, it’s clear to see that the outcomes from this particular phase of the study have been promising and certainly will encourage further testing to confirm these results. The researchers will also need to study potential harmful side-effects at high doses that this report threw up; especially in patients who had a particular genetic predisposition to Alzheimer’s. Since these side effects tended to show up at certain dose levels, the researchers might be able to use further studies to refine these doses and make the drug more patient-friendly.
Too soon to be excited?
Crucially, it needs to be confirmed over longer studies that a treatment which clears Aβ plaques will help with cognitive decline.
As mentioned above, the amyloid hypothesis is only one of many potential causes for Alzheimer’s, and it may be shown over time that this is not the best route to tackle the disease, or indeed that multiple causes must be dealt with simultaneously to be successful in the battle against this disease. More research and further rounds of clinical trials will have to be carried out before aducanumab would actually become commonplace for treating Alzheimer’s patients. Luckily, some of these trials are already ongoing, including a long-term extension trial which will use some of the same subjects as the study being reported on here, and will give a better idea of the long-term effects of treatment with aducanumab. Phase 3 developments are also under way. As you can see from the chart below, this means that at the most optimistic estimate, aducanumab would not be available for another 4-5 years, and could potentially fall at one of many hurdles in the meantime.
Breaking ground with Alzheimer’s research
It is sobering to think that in the modern age, when instant access to information is taken for granted, there is still so much left to understand about a disease which affects so many. Yet at the same time it is reassuring that so many are dedicating their lives to the pursuit of answers, and that there are a number of possible different routes to the disease; or even as we may come to discover, from a combination of more than one of these possible routes. It might be too soon to get really excited about Sevigny et al’s study, but it is certainly not too soon to feel optimistic about the future of treating this disease and the wealth of information being amassed. Plenty of researchers out there are breaking ground each day, little by little, in the search for a cure.
Are you, or is someone you know, worried about Alzheimer’s and how it might affect you? Contact the Alzheimer’s society for help and information, or to get involved in fundraising.