The last year was clearly dominated by COVID-19, not only on a personal but also a scientific level. The focus on COVID-19 science and that we all seem to be these days expert epidemiologists and virologists, somewhat blinkered other scientific advances – including in dementia science. Of course, many dementia scientific studies had to stop because of COVID, since people with dementia are the most vulnerable for COVID, nevertheless, many studies and clinical trials continued for dementia.
Below I will review my personal highlights of the main biomedical dementia science advances and findings in 2020. In particular, I want to highlight three biomedical areas: 1) Therapeutics, 2) Biomarkers, and 3) Neuroinflammation. None of these topics is entirely new but 2020 has seen major advances for dementia science in all three areas.
Let’s explore each in turn.
The therapeutic/pharmacological development of Alzheimer’s disease-specific medication has made leaps and bounds over the last year with several medication candidates showing promising findings in initial clinical trials. This contrasts starkly with the previous decades when most clinical trials for Alzheimer’s disease only showed negative results.
However, these positive findings were mostly overshadowed by the drama – and I am mean DRAMA – around the approval of the first Alzheimer specific drug – Adacunumab by Biogen. Adacunumab is a so-called monoclonal antibody treatment for beta-amyloid (beta-amyloid is one of the main proteins responsible for Alzheimer’s disease). Without going into too much detail, monoclonal antibody treatments work by helping or ‘priming’ our body’s immune system to remove excess beta-amyloid from our brains, therefore reducing our risk of developing Alzheimer’s disease in the future. It is to date the most promising approach to ‘treat’ Alzheimer’s disease pathophysiology and there are several trials currently underway, including from pharmaceutical companies such as Roche and Eli Lilly, which use similar principles.
Most of these monoclonal antibody treatments for beta-amyloid show a slowing down of the disease progression and symptoms if people are identified early enough. There has been limited evidence so far that these drugs work if we have already Alzheimer’s disease but they show good effects in Mild Cognitive Impairment or at-risk people. It clearly shifts the focus on early diagnosis of Alzheimer’s disease, since these therapeutics, as well as lifestyle changes, are most effective before people have full-blown Alzheimer’s disease.
What’s the drama then, if everything looks so promising?
The drama arose during the certification process for Adacunumab. Every new medication after it has been tested in clinical trials needs to be certified by an independent body before it can be released to healthcare systems for potential use. There are different organisations in different countries which approve new medications, for the US it is the FDA (https://www.fda.gov/home), for the UK it is the MHRA (https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency), for the EU it is EMA (https://www.ema.europa.eu/en) and so on. These organisations ask the pharmaceutical companies to provide the full data for the drug to be approved, including clinical trials. The data is then checked by the organisation itself (FDA, MHRA, EMA etc) as well as a group of independent scientists who were not involved in any of the drug development or trials of the new drug. Finally, there is a meeting, when the pharmaceutical company, the approving organisation (FDA, MHRA, EMA etc), the independent scientists and patient advocates come together to discuss all the information and issue a recommendation for approval – or not.
Usually, these recommendation meetings are fairly formulaic, if not boring, affairs, as any new drug development reaching this stage is highly likely to be approved. The reason is that to come to this meeting, any new drug has to have shown very convincingly that it works. However, it is this meeting where the drama around Adacunumab unfolded. The reason is that the scientific and clinical trial data for Adacunumab looks, in fact, pretty weak, which has been a concern of the scientific community for some time. However, Biogen and FDA were keen to get the new drug approved, which was further supported by the patient advocates who are keen to see the first drug against Alzheimer’s disease available. But they had not considered the vociferous challenges the independent scientists made at that meeting. During that meeting, the scientists ‘took apart’ the Biogen data, showing Adacunumab has shown very little effect in reducing the progression of Alzheimer’s disease. Indeed, the 11-strong scientific panel voted 10-1 against the approval of Adacunumab. They further questioned a ‘too close relationship’ between Biogen and the FDA, which resulted in the new drug suggested for approval while the science was not strong enough.
Now the scientists can only recommend to the FDA what they should do, but in the end, the FDA can ignore the scientists’ recommendation, in particular as there is such a strong patient advocate push for a medication. Still, it is pretty much unprecedented to have such a scenario and raises a lot of questions. The FDA will make its final decision on March 15th 2021 as to whether Adacunumab will be approved or not for use in the US. The MHRA and EMA will likely pay close attention to the FDA decision.
It raises the question as to whether we would personally take (or even pay for) a drug which has shown only little scientific effect. The words ‘false hope’ comes to my mind in this context…
But let’s not be too downcast by the Aducanumab drama, as I mentioned there are several promising drugs now in development, which means that we will likely see the first Alzheimer’s disease drugs emerging on the market over the next 2-3 years. That is exciting and good news as to date our best ‘treatment’ options are to change our lifestyle to slow down the onset of Alzheimer’s disease. Don’t take me wrong, lifestyle changes have been shown to be very powerful by reducing our risk for developing dementia by up to 40%. However, for the future, we have ideally combined lifestyle and pharmaceutical treatment approaches towards the slowing or prevention of Alzheimer’s disease will have a major impact on our ageing societies in the future.
The other keystone for identifying people at-high-risk of Alzheimer’s disease are biomarkers. Biomarkers are any techniques which can identify the accumulation of the proteins in dementia, potentially before symptoms develop.
If Alzheimer’s disease therapeutics have made big leaps in 2020, then biomarkers are moving at lightspeed. In fact, it is quite hard to keep up with the research development of blood biomarkers in particular, as the field is moving so fast. Blood biomarkers were seen for many years as too difficult to develop for Alzheimer’s disease (see also my recent blog entry on this topic: https://dementiascience.org/2020/12/14/blood-tests-for-alzheimers-disease-are-they-becoming-a-reality/), but not anymore. Taking a simple blood sample will allow in the future determine quite precisely whether any of us is at an increased risk of Alzheimer’s disease and receive then the appropriate treatment.
These blood biomarkers are currently targeting particularly two proteins involved Alzheimer’s disease – amyloid and tau. Beta-amyloid blood plasma biomarkers are now fairly established and will soon the commercially available (some are currently undergoing the certification process for being used in healthcare). However, the plasma blood biomarkers for tau have made the biggest advances in 2020, with two competing tau biomarkers (p-tau 217, p-tau 181) ‘slugging it out’. Both markers have been shown to be more sensitive in detecting Alzheimer’s disease pathology than other biomarkers (such as structural brain imaging or cognitive changes). Indeed, p-tau changes have been observed in people with familial Alzheimer’s disease, 22 (!) years before they develop symptoms. Having such blood biomarkers would therefore clearly ‘shift the goalpost’ in the diagnosis of Alzheimer’s disease, allowing earlier treatment and potentially reduction or even avoidance of significant symptomology. Exciting times indeed!
The other biomarkers which have made progress in 2020, are Positron Emission Tomography (PET) biomarkers. I recommend reading my article on brain imaging in dementia (https://dementiascience.org/2020/12/07/how-does-brain-imaging-help-with-dementia-diagnostics/) to understand how PET works. Instead of using blood samples, PET biomarkers use brain imaging to detect the earliest protein accumulations. The PET biomarkers for beta-amyloid have again been established and validated for a few years, with several clinical centres in the world using these scans for their diagnostics of people with dementia. However, the tau PET biomarkers were still less reliable and research in 2020 was focused on developing more specific tau PET biomarkers. Previous tau PET biomarkers (such as Flortaucipir) seem to be less specific to tau changes in Alzheimer’s disease, instead, these biomarkers attached themselves often to other brain tissues as well, making it much harder to determine whether the brain imaging changes are really due to Alzheimer’s disease. New PET biomarkers (such as MK-6240, PI-2620 and APN-067; one always knows that findings are really novel in science when there is no proper name yet and instead incomprehensible acronyms are used instead of words), seem to attach much more specifically to tau in the brain and can even detect different versions of the tau proteins. This would clearly improve such tau PET biomarkers.
But why would we need brain imaging biomarkers if we have blood plasma biomarkers, which are much cheaper and easier to obtain?
A fair question, however, we should remember that for blood plasma biomarkers we only get a ‘proxy measure’ indicating Alzheimer pathophysiology in the brain but we do not know where in the brain the pathology is or if it might be due to another reason. PET biomarkers are, therefore, albeit more expensive and less accessible, more specific. In the future, it will be likely a hybrid approach for diagnostics where the majority of people will have a blood test for Alzheimer’s diagnostics with only people where the blood test is unclear receiving a PET brain scan. But I guess time will only tell how these new biomarkers will be used in the future.
The final ‘hot’ topic of 2020 has been neuroinflammation. Neuroinflammation is not necessarily a new topic as people have been interested in its impact on dementia for several years. However, last year research into neuroinflammation made further big inroads.
What is neuroinflammation in dementia?
Neuroinflammation means how the brain’s immune system reacts to the protein accumulations in dementia. When too much protein accumulates, the immune system gets activated and in particular, one type of brain cell (microglia) become active to try to remove the excessive proteins. However, if the protein accumulation continues, the microglia gets over-active (hyperactive) and starts damaging the actual nerve cells as well. Instead of slowing down the disease process, a hyperactive immune system can in fact ‘fan the fire’ for dementia, as it damages the nerve cells further.
Microglia activation and its activity has become, therefore, a big topic in dementia research over the last few years and more so in 2020. Research in the last year has increasingly shown that microglia might not only be reactive to the protein accumulation and but could also foster it. It further emphasises how important neuroinflammation is as a contributing factor to the dementia processes. It also explains why other environmental factors, which contribute to neuroinflammation can increase our risk of dementia. For example, it has been known for quite a while that chronic inflammatory conditions, such as rheumatoid arthritis, can increase our risk for dementia later in life significantly. Interestingly, people with rheumatoid arthritis who are on anti-inflammatory medication, show a reduced risk for dementia, further showing that if inflammation is controlled our risk for dementia might be overall reduced.
Two new areas have been gaining particularly attraction in this regard: football and air pollution. There has been for years investigations into how head injuries and concussion caused in sport, trigger a neuroinflammatory response and hence increase our risk for dementia. Indeed, in the US, the American Football league (NFL) has even been sued by former players who have developed dementia, which they argue was due to head injuries and concussions during their time as players. A similar argument has now come up in England within the professional football (soccer) league, where several high-profile former football players have developed dementia or died of it. Concussions are much are rarer in football (soccer) than in other contact sports, however ‘heading the ball’ emerges as the potential culprit for the increased risk of dementia in football players. The theory is that repeated heading of footballs might cause a ‘sub-concussive’ syndrome, leading to a neuroinflammatory response in the brain each time a ball is headed and potentially increasing the risk for dementia. The increasing public scrutiny of heading in football and its potential relationship to neuroinflammation has therefore become a hot topic and several studies have started investigating the link between football and dementia risk. (In case you are interested, I am involved in one of those projects: https://www.scoresproject.org/).
Air pollution has become the other hot topic in terms of neuroinflammation. There have been for years suggestions that small pollution air particles – so-called PM2.5, particles less than 2.5 microns in diameter – can cross the blood-brain barrier and enter the brain. The blood-brain barrier protects our brain so that no ‘foreign’ molecules can enter, however, PM2.5 particles can cross it. The original finding of the link between air pollution and risk for dementia was actually not made in humans, but dogs, or more specifically stray dogs in Mexico City. A study investigating these dogs found that most of them developed dementia and it was theorised that because they were exposed to such a large degree to PM2.5, as they spend most of their times at congested streets in the height of car exhausts that it was actually the air pollution which caused their dementia changes in their brains. These findings were regarded as fanciful by some at the time, but there is now increasing evidence in humans as well that PM2.5 can increase our risk for dementia. Several studies in 2020 have demonstrated that people who were exposed or living in areas with higher levels of PM2.5 in the air are at an increased risk for dementia. The theory to date is that PM2.5 triggers a neuroinflammatory response which in turn increases our risk for dementia. There will be clearly much more research in this direction to find out whether these changes caused by air pollution are permanent or can be reversed. However, the preliminary findings are concerning enough for an international commission to add air pollution as a risk factor for dementia.
There were plenty of other interesting developments in 2020. One I would like to mention is as to whether dementia can be actually infectious to other people. This seems a strange concept, but over the decades there have been always rumours that this might be the case. An international commission decided, therefore, to review all the evidence and cases of such reports. They found that there is no indication of dementia being infectious. If you want to find out more about this topic, I recommend you read my blog entry on this topic (https://dementiascience.org/2020/10/20/is-alzheimers-disease-infectious/).
Finally, the ‘elephant in the room’ for dementia research in 2020 is how COVID-19 affects dementia risk and people with dementia. Research in this direction is still very new and ongoing. So far, findings have ‘only’ shown that COVID-19 has worse consequences for dementia than for people at a similar age. At the moment, the reason for this worse outcome for people with dementia is that often people with dementia have a compromised immune system, especially later in the disease. This means that their immune response, which is already pre-occupied with the protein accumulation is less able to fight the COVID-19 infection. In turn, this makes it more likely that people with dementia who are infected with COVID-19 have worse outcomes. But as I said, this is a matter of ongoing research and we also do not know how ‘long COVID’ might affect dementia and the risk for dementia in the long-term. Something to watch out for in 2021.
Overall, 2020 has been a good year for dementia research, even with COVID causing a major disruption to research projects and clinical trials. The enormous advances for pharmacological treatments and biomarkers are very positive in my opinion, as it will allow to detect people at risk of dementia earlier and treat them for Alzheimer’s disease. Neuroinflammation is the hot topic at the moment in dementia research and can potentially explain why people are at a higher risk of dementia, in particular if they have repeated neuroinflammatory episodes in their life. It could also explain why some people with dementia progress much faster than others, as they could have a stronger immune response which attacks the nerve cells. There is clearly a lot to do and understand but from a biomedical research perspective, there is ‘light at the end of the tunnel’ with 2020 showing again how much better we are now at preventing, diagnosing and potentially treating dementia.