Amyloid plaques (stained brown)
Dear Readers, it might not seem like a cheerful subject for a sunny Easter afternoon, but as I come towards the end of my Cell Biology course with the Open University, we are being asked to investigate various neurodegenerative diseases. I opted for Alzheimer’s disease – while Dad had vascular dementia rather than classical Alzheimer’s, there are many reasons to suspect that the division between these two forms of dementia is not as clear cut as we used to think.
Traditionally, Alzheimer’s disease was blamed on two types of malfunctioning protein. One, known as beta-amyloid, is usually an inoffensive little molecule that helps with passing signals between various parts of the brain, but in Alzheimer’s it doesn’t fold properly, and instead of being a little short chain it becomes a ‘plaque’, an aggregation of cells that finds its way into the synapse, which is the gap between nerve cells (neurons). This gap is essential for signals to pass properly, but if it’s blocked the signals can’t get through, and the neuron degenerates and eventually dies. These plaques were first seen in the brains of Alzheimer’s patients back in 1911 when they were first identified by Alois Alzheimer. Of all the routes to immortality, being named after this dreadful disease must be one of the saddest.
The second protein is known as tau. Typically, this helps to stabilise the structure of the cytoskeleton within the cell – you might remember my little film of a motor protein making its way along the ‘roadways’ of the cytoskeleton a few weeks ago. However, in Alzeheimer’s disease these proteins malfunction and form what are known as ‘neurofibrillary tangles’ (or NFTs for short). So, instead of forming handy transport pathways so that nutrients and waste products can be moved about in the cell, the tau proteins form a knotted mass, which again results in the death of the neuron.
Neurofibrillary tangle
However, as usual things are not quite as simple as they seem. In a long-standing project known as the Nun Study, a group of nuns kindly agreed to donate their brains to science after their deaths. The nuns were visited regularly, and performed a range of cognitive tests to see how they were doing. When scientists looked at their donated brains after they had died, they found something surprising – some of the nuns who had performed very well on cognitive tests had a high incidence of beta-amyloid plaques and NFTs, while some of the nuns with the worst cognitive results were relatively clear of these features.
What was going on?
One clear factor that impacted on those with the worst cognitive results were incidences of ‘vascular events’, such as strokes or heart attacks. It’s not well-known that one of the many, many side-effects of smoking is vascular dementia, because of its long-term effects on the blood supply to the brain. As my Dad smoked 20 a day until he was in his eighties, it’s highly likely that the smoking was a key factor in the stroke that he had in 2004, and that this was a key factor in his dementia.
However, clearly this isn’t the whole story either – fortunately, many people who have suffered strokes do not go on to develop dementia, and not everyone who has Alzheimer’s has had a stroke. Another area that scientists are looking at is the whole science of bioenergetics, and if the very name makes you want to move on to something less taxing, let me explain.
Our brain in general, and neurons in particular, require a great deal of energy – although our brains only account for 2% of our body weight, they use up to 25% of our energy. As we get older, the parts of our cells that make most of our usable energy, the mitochondria, become more prone to damage and less efficient, so our neurons start to struggle to find enough ‘fuel’. The neurons also become less efficient at dealing with what are known as ‘Reactive Oxygen Species (ROS) – I was more familiar with them as free radicals, chemicals that are implicated in all sorts of cell damage and inflammation. Finally, the damaged and dysfunctional mitochondria would normally be cut up, packaged and removed from the cell by a bunch of proteins called proteases, but these also become less efficient as we get older. All in all, it’s not a pretty picture, though it is a very variable one. For example, there’s a theory that women (who make up two-thirds of all Alzheimer’s patients) might be protected from a lot of this damage by oestrogen and progesterone, until we enter the menopause. On the other hand, women also tend to live longer than men, so it might just be that, as Alzheimer’s is overwhelmingly a disease of older people, we live long enough for it to develop and become apparent.
So, all in all we have learned a lot about the possible causes of Alzheimer’s disease, but not what to do about it. For a long time, scientists hoped that something that would prevent the formation of the beta-amyloid plaques would also stop the development of the disease, but this proved not to be the case (as we’ve seen, the causal relationship between the plaques and Alzheimer’s is sketchy at best). Currently, there is a lot of interest in the area of malfunctioning mitochondria, and if anything can be done to either reduce this, or to improve the way that the body deals with the problem. There is also one particular gene which massively increases a person’s chance of contracting Alzheimer’s, so there is concentrated work going on look at how this can be rectified. At the moment, though, the best way to try to stave off Alzheimer’s, and the other forms of dementia, seems to be to do the things that will help with everything else – keep active, keep interested in the world and keep engaged with friends, family and the wider community. A key finding of the Nun Study was that where there was a high level of complexity, fluency and vivacity of the writing of the nun, there was a lower level of cognitive decline, which I find rather hopeful – an optimistic attitude also seems to have staved off the worst symptoms of dementia. Of course, we all know lovely, positive, happy people who have ended up with dementia, so this is not an absolute, or a preventative, but I do suspect that the mental stimulation that comes from the exchange of ideas may at least help to keep the wolf of Alzheimer’s from the door for a little longer.
None of us know if we’re going to end up with dementia in one form or another, but there is much to be said for living the richest, most meaningful life that we can while we can still live it.
Very interesting.
Thank you Bugwoman for this fascinating and well-informed read. My Dad developed dementia slowly over many years and then quickly over the last few. It began with forgetfulness and confusion but later he didn’t recognise anyone, could not recite sequences and believed that he was a.small child. He was also very truculent, said very unpleasant things and was threatening towards my late mother. It was an exceedingly stressful time for our family.
My Dad was diagnosed with low grade lymphoma which was later described as mantle cell lymphoma. When I spoke to the coroner after his death, he told me that this has been the cause of the rapid decline in his condition. I had no idea that cancer can also be a factor in the progress of dementia.
My Dad used to be sharp as a pin. He could remember so many things, he would always complete crossword puzzles and loved the TV shows Countdown and Mastermind. His decline was very distressing to see. I became: ” That nice lady from over the road.” He told me Mum that he had no idea why I visited every day. He wondered when his parents were going to pick him up from the nursing home, until I reminded him that they didn’t have a car.
Dementia is so very stressful for families, anything that can be done to reduce its incidence and severity would be a beneficial development. The nursing home that he was only in for two weeks before he died, was a wonderful place and he was happy there. I do think good care is another very important factor.
A close friend’s Dad has just received a diagnosis of dementia. He has seen the path that we walked and has decided to retire with immediate effect, to support his parents. We will be there for him as he has been for us. This is indeed a very cruel disease.
Hi Christine, the cost of dementia on everyone who loves the person so afflicted is so underrated, I feel – I’m so glad that your Dad had a good nursing home for his last few weeks, the place my Dad was in for his last eighteen months was wonderful, so good in fact that for most of the time he thought he was on a cruise. He, too, varied in the age that he thought he was from a small child to a man in his thirties, even though he was eighty-five when he died. At his last Christmas he insisted that his Mum and Dad (who had both died years earlier) were coming to dinner with us, and he was most upset when they didn’t show up. I wonder now if it was a sign that he was getting closer to the end – he died in March 2020, just as the pandemic lockdown had started, but I was lucky enough to be able to be with him.