– Dementia and its prevention

Having decided that everlasting life is impractical, we can still use existing knowledge to improve our survival. But we want our extra years to be enjoyable, and that won’t be the case if our brains fail us. Just as hearts, kidneys and livers fail in old age, brains do as well. We call it dementia.
Dementia can be caused by several diseases; the commonest are Alzheimer’s disease, and vascular (multi-infarct) dementia.
Our nervous systems – the brain spinal cord and peripheral and autonomic nerves – are infinitely more complex than the heart and circulation, and are very much more specialised so that repair is much harder. We have much less understanding of how the brain actually works, than the heart or the liver for example. But progress is being made.

So what are the risks of getting dementia? The first is obviously getting older -the older we get the more likely we are to get it. About one in 12 people age 65 will develop Alzheimer’s disease and at age 85, one in three will be affected.
But there is not much we can do about this, as the alternative is worse – dying young. So what can we do to lessen the risks to our brains, as we get older?

Considering vascular dementia first, over time damage to the brain is caused by interruptions n the blood supply, due to damage to the walls of arteries. The resulting lack of blood supply to brain tissue means it is starved of oxygen, and so the brain tissue is damaged. This is the same sort of damage which causes heart attacks, where heart muscle is damaged due to blockage of arteries in the heart. In the brain it shows up as a series of small strokes. The area damaged by lack if blood supply in both cases (brain and heart) is called an infarct, and hence vascular dementia is sometimes called multi–infarct dementia, and may be prevented to some extent by lowering cholesterol, treating high blood pressure, good control of diabetes and keeping weight down, in the same way as heart attacks can be prevented. Statins, well known in preventing heart attacks and some strokes, should help.

However, more often, dementia is due to Alzheimer’s disease, which is a specific disease not due to any form of hardening of the arteries. It is associated with plaques of a tissue called amyloid building up in the brain especially the amygdala (a part of the brain associated with putting down memories). Alzheimer’s disease is usually the late onset or “sporadic” type, which usually develops after age 65, but there are some inherited forms which occur earlier, sometimes as early as the mid fifties. I had a patient once who had it in her fifties, and as it progressed she had to go into the community home where she had worked as a social worker. She thought she was still going there to work even when she did not know who her husband was and completely incapable of managing on her own. The staff that had worked with her before were very caring but it was gut-wrenchingly sad. She died in her early sixties. The familial type of Alzheimer’s disease has certain genetic markers, and there are clinical trials are now going on with some families, looking for specific changes that can be made while the patient is still in the asymptomatic phase of the illness.

We know that some genes, such as Apo E, may influence Alzheimer’s disease risk. Apo E-4 has been found in around 40% of people with Alzheimer’s disease, and may lower the age at which it starts. But many with the gene never develop Alzheimer’s disease and many who do develop it do not have the Apo E-4 allele. Also there may be additional risk factor genes for Alzheimer’s disease. So most of us have no way of knowing at what age we will get Alzheimer’s, or if we will get it at all.

So can we try to prevent it happening?

If you have high blood pressure, high cholesterol, diabetes, or have had heart problems, you should already be taking medication for these conditions, including statins. All these should reduce the risk of getting vascular dementia. And the lifestyle choices you make should be obvious too – not smoking, healthy diet, plenty of exercise. However Alzheimer’s disease is not related to problems with your blood vessels and atheroma. So what lifestyle measures should you take to reduce your risk of developing this?

Alzheimer’s disease takes many years to develop – possibly 10-20 years or more, so there is plenty of time for individuals to try to reduce their risk. The good news is that the simple things I have been talking about in this blog can help. This isn’t just wishful thinking. In a recent study in the Lancet it is estimated that up to 1 in 3 cases of Alzheimer’s disease maybe preventable by lifestyle changes. According to this report, there are eight potentially modifiable risk factors that have consistent evidence of an association with Alzheimer’s disease; lack of exercise, diabetes, high blood pressure in middle age, obesity in middle age, depression, smoking, low level of education, and traumatic brain injury.

The importance of each individual risk factor depends on where you live. Worldwide, the highest estimated risk in populations was for low educational attainment, 19·1%; but for the USA, Europe and the UK it is for physical inactivity: USA 21·0%, Europe, 20·3%, and the UK, 21·8%,

So for western countries the most crucial risk factor is undoubtedly lack of exercise, and this in theory should be easily remedied.
It is amazing how sedentary people can be. Watching TV, using the computer, doing games, all mean sitting around, and going anywhere often means using the car. We know that taking exercise, at least 2 hours every week (walking, cycling, swimming) is key to preventing diabetes, high blood pressure, and obesity. But it is also associated with better brains – one study reported that there was a 50% reduction in the risk of dementia in older persons who maintained regular bouts of physical activity.

Several studies have followed up groups of older patients, some who had healthy lifestyles and some of who did not, and measured their physical and cognitive abilities over time. Evidence over the last 5 years suggests that modifying these behaviours can affect brain adaptability (plasticity) in both humans and animals. Other positive benefits may include a decrease in the risk of falls, improved mood, and potentially, perseveration of brain function. These can be long lasting.

Eating healthily with plenty of fresh fruit and vegetables is very important. Recently, there have been several meta-analyses of studies on diet and the development of dementia, although unfortunately the articles do not distinguish between vascular dementia, which should theoretically be reduced by a healthy diet anyway, and Alzheimer’s where there is no theoretical reason why diet should help, so the benefit such healthy eating may mainly come form the effect on vascular dementia. There again, Alzheimer’s disease accounts for about 80% of all dementia, so a decrease overall it would indicate that Alzheimer’s too might be reduced. Published results are that higher consumption of unsaturated fatty acids and antioxidants decrease the risk of dementia, while smoking and higher consumption of aluminium increase the risk. Supplementation with B vitamins may have an effect – they do in one series and not in another. The Mediterranean diet had a small effect on reducing dementia, and the effect of fish, vegetables, fruits, and alcohol was said to need further investigation. Low levels of vitamin D were associated with cognitive decline, although this may well be an association rather than a cause as low vitamin D levels are a marker for poor health.

What about low educational attainment, which has the biggest association with Alzheimer’s disease in the world as a whole? The association has been known for a long time, since 1988 in fact. One American study (the well known Framingham study) found that it may be a spurious connection – that people with lower educational attainment smoke more, and have a worse diet, and this is reflected in a higher incidence of vascular dementia, and that there is no effect on true Alzheimer’s disease. But if you take a code for overall dementia such as ICD-9 or ICD-10, and correct for these factors, then the association is very clear. A meta-analysis in the World Alzheimer Report 2014 on Dementia and Risk Reduction, suggested that the reduction in risk may be around 40%.
So what could cause this?
There are several hypotheses. People with higher educational attainment are likely to have a higher socio-economic status, to enjoy a healthier and more advantaged lifestyle, and to have greater access to superior healthcare. There is undoubtedly something in this explanation, which is related to the explanation of poor diet and smoking in those whose education is limited. But a further explanation may lie in the “brain reserve theory”, which is that a bigger reserve function has been built up over years of intellectual effort, developing a greater complexity and/or efficiency of neural network. Then as dementia-related pathology occurs in the brain, people with higher levels of education may actively compensate by drawing on a greater reserve of cognitive processing approaches – getting round problems of cognition as they occur. This might happen in people who happen to have bigger brains too.
Then there is the ‘use it or lose it’ hypothesis: Lifelong cognitive activity may be necessary to help prevent cognitive decline, and those with higher education may be more highly motivated to pursue intellectual stimulation throughout the life course. Other scientists say that the testing of people with low educational skills is not accurate enough to distinguish between early dementia and a basic inability to do the tests. Or that low educational attainment is a function of low intelligence, which may be associated with other pathologies. So more research into what exactly is causing this association with educational attainment and reduced risk of dementia is definitely needed.

But at the very least, keeping mentally active seems like a good idea, with activities such reading and writing for pleasure, learning foreign languages, playing musical instruments, taking part in adult education courses, being both pleasurable and good for you. Sports such as playing tennis, walking, golf, swimming and group sports, such as bowling will help you keep your muscles from wasting as well improving your brain and co-ordination. It seems that bilingual people who use both languages do better if they do develop Alzheimer’s because their brains have more “pathways” which can be used to get around damaged areas.
Interventions such as “brain training” computer games have been shown to improve cognition over a short period, but research hasn’t yet demonstrated whether this can prevent dementia.

All this may be a little bit comforting for those of us with an intellectual bent. But I always remind myself that the end of the process of dementia of whatever cause, is that everything goes, all memories, all skills, and all personality. It is a devastating disease however brilliant you may have been. Even code breakers at Bletchley can get it, despite an impeccable lifestyle, and constant honing of lifelong learning and skills. These risk factors and benefits are only associations with changes in the risk of dementia, and at the most one could expect these efforts to slow down the effects of dementia or delay them; they cannot completely prevent it.

So we hope there will be some treatment if we do get it. Certainly this would be a game changer. An effective treatment for AD is perhaps the greatest unmet need facing modern medicine, preventing so much anguish and suffering as well as saving vast amounts of money that could be put to more productive use. Even a five-year delay in the onset of symptoms of Alzheimer’s disease could greatly reduce the number of people with the disease.

As with research into ageing more generally, there are lots of different ways of tackling the problem.
The first medications specifically for treating Alzheimer’s, the anti-cholinergics, came out in the early 2000’s, and I do remember all the fuss. They were very expensive and so a way of rationing them had to be found because so many patients were clamouring for them, not surprisingly. So clinics were set up so that patients would be treated only if they were at certain stages in the disease. Patients and their relatives got very angry when they were denied them because they thought the drugs were a real advance which could stop the progress of dementia. But soon I realised that this was really a triumph of hope over experience, or alternatively an example of how the pharmaceutical industry overplayed its hand). As their doctor I couldn’t see any benefit in my patients who took the medication, though sometimes relatives said they saw a difference. But the drugs didn’t alter the overall trajectory of memory loss and loss of function. Eventually the demand died down and they eventually became quite cheap as the patents ran out, but it had been a completely false hope.

Very recently it has been confirmed that statins, these wonder drugs that have prevented many cases of heart disease, can also be associated with a reduction of risk of getting Alzheimer’s. One would expect that they would have an effect on multi-infarct (vascular) dementia and all patients at risk of this should already be taking them. But this study shows that there is a small association between taking some statins (not all) and a decrease in the number of patients getting Alzheimer’s. Researchers reviewed 400,000 patients and say the effect of statins may be explained by an interplay between cholesterol and beta-amyloid, which plays a role in dementia, or that statins’ anti-inflammatory properties could be preventing the disease. Or there may be other reasons for the association. The way to test this is to look at prospective trials, following up patients who are taking them and comparing the rate of development of Alzheimer’s with those who don’t, after controlling for other factors. I don’t know whether this is being done. It is a small decrease and is not seen in all people, but some people might want to take the appropriate statins

In 2016 several more drugs, monoclonal antibodies, have been tested. Monoclonal antibodies are a huge development in many diseases because they can accurately target and destroy specific proteins, and are used in cancer, auto-immune diseases and many more. Research is progressing in development of monoclonal antibodies against amyloid β, the protein that seems to be awry in Alzheimer’s disease. They have not been universally effective in Phase 3 trials with people with mild, prodromal, or even preclinical AD, but some have shown good effect. Many other novel drug treatments are being studied, but the time for data analysis and confirmation is typically 4 to 10 years.

It isn’t the magic bullet we are hoping for. Indeed, pharmacological interventions have been disappointing so far, but we can but hope.

References.
Journal of Alzheimer’s Disease, vol. 22, no. 1, pp. 205-224, 2010
Molecular Neurobiology November 2016, Volume 53, Issue 9, pp 6144–6154 Dietary Patterns and Risk of Dementia: a Systematic Review and Meta-Analysis of Cohort Studies
The Lancet Neurology DOI: http://dx.doi.org/10.1016/S1474-4422(16)30356-8
The Lancet Neurology Volume 13, No. 8, p788–794, August 2014
Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data
33. Mortimer J. Do psychosocial risk factor contribute to Alzheimer’s disease? Etiology of dementia of Alzheimer’s type