The Conversation

In 2022, Prof Marcus Richards and Prof Jon Schott wrote a piece for “The Conversation”. The following is an extract from this article, which focused on the mental ageing and cognition work. To read the full article: https://theconversation.com/weve-been-studying-the-same-people-for-76-years-this-is-what-weve-found-out-about-alzheimers-disease-183949

What is dementia?

Dementia is an ancient word meaning “out of mind”, but today it refers to a syndrome of acquired (not present from birth), progressive cognitive impairment, severe enough to interfere with everyday activities such as planning meals, managing bills and medicines, and housekeeping.

As cognitive impairment worsens, these activities become more impaired, eventually disrupting basic self-care such as dressing and bathing. Sometimes this is accompanied by depression, paranoia, aggression, wandering or reversed sleep-wake cycles. Dementia is therefore very different from the mild cognitive changes that occur in normal ageing.

Alzheimer’s disease is the commonest form of dementia. On a biological level, a key process is the depositing of beta-amyloid protein in the brain. This is a protein that comes from the fatty membrane surrounding nerve cells. It is chemically sticky, gradually clumping together and interfering with nerve function and triggering inflammation. These clumps gradually gather between the nerve cells in the brains of people with Alzheimer’s disease and become plaques – hard, insoluble accumulations of beta-amyloid proteins.

These plaques are thought to be an early hallmark microscopic feature of Alzheimer’s. However amyloid plaques in themselves are not sufficient to cause dementia which is more closely related to accumulation of another, likely downstream, protein called tau which clumps within nerve cells in the form of tangles.

Accumulation of these proteins leads to nerve cell death which leads to brain shrinkage (atrophy) which can be seen using MRI scans. The diagnosis of Alzheimer’s dementia remains predominantly clinical, requiring evidence of decline over time in at least two cognitive areas, such as memory, language, attention or problem solving. Contemporary criteria also involve investigations including MRI or CT brain scanning and, in some cases, spinal fluid or positron emission tomography (PET) scans. PET scans can be used both to visualise and quantify abnormal protein deposition within the living brain. For Insight 46, we use a tracer that is injected into the body, enters the brain and which highlights where any amyloid is accumulating.
Alzheimer’s disease is only one of many forms of dementia. Other causes include other neurodegenerative disorders due to the accumulation of different proteins, and cerebrovascular disease where the blood supply to the brain is interrupted, for example, from blood vessel narrowing, blockage or bleeding.

What have we found so far?

1. Amyloid accumulation starts before symptoms

We found that around 18% of “cognitively normal” people from the cohort had amyloid PET scans like those seen in people with Alzheimer’s disease – a finding that tallies with other studies in people around the world who don’t have symptoms. These individuals also had slightly lower performance on sensitive tests of cognition and slightly increased rates of brain shrinkage.

While the significance of the finding for amyloid frequency is unclear – and hence our protocols and consent processes mean that unlike some MRI findings we do not give the results to participants – we think that these individuals are at higher risk of developing cognitive impairment in the future, something we plan to look out for closely in the years to come.

2. Child cognitive tests indicate brain function later in life

We found that cognition assessed in childhood predicted cognition around 60 years later. This is consistent with earlier findings for the whole cohort, suggesting that some aspects of cognitive performance are stable over a lifetime. This matters because cognitive function is not just about the mind – it helps to shape everyday skills, supports quality of life and ultimately predicts how long we live.

However, the level of cognitive performance can be potentially improved. In the same report, education and occupation in midlife predicted later cognition after taking account of childhood cognitive scores. We had seen this in the whole cohort too, which counters an old argument, still sometimes made, that education is nothing more than a marker of IQ. In other words, level of education and type of occupation can positively affect cognitive performance in later life regardless of cognitive skills in early childhood.

It also emphasises that education does not just increase opportunities but has a significant effect on brain health.

3. Importance of early heart health checks

Some of the first publications from Insight 46 showed that high and rising blood pressure in those aged in their 40s and – in some cases their 30s – predicted smaller brain volume. There are several possible mechanisms for this, including microstructural damage from high blood pressure and a higher burden of small blood vessel damage in the brain. The latter is thought to be a marker of brain frailty, raising the risk of stroke, dementia, depression, impaired mobility and death.

Similar outcomes were seen in relation to heart health in general, using an index that includes blood pressure, use of anti-hypertension medication, diabetes, smoking and high body weight. Conversely, falling blood pressure in later life may in some cases be a marker of poor brain health.

Similar findings may also apply to body weight. A follow-up analysis found that declining body weight in the two years before the scan predicted amyloid.

These findings have significant implications for public health, suggesting that routine checking of heart health, and blood pressure, in particular, may need to start much younger than is typically recommended – probably at or before the age of 40.

4. A blood test for Alzheimer’s disease

Most experts will agree that when we have new drugs for Alzheimer’s disease, they are likely to have maximum benefits if taken early in the disease, and preventing the onset of cognitive decline would clearly be preferable to trying to slow or halt memory decline that has already started. It is unlikely that the expensive PET scans we are conducting in Insight 46 will be able to screen whole populations, so there is much interest in developing blood tests instead.

Using state-of-the-art methods sensitive enough to detect 1g of salt dissolved in one million trillion litres of water, we were able to show that a blood marker is capable of detecting amyloid in the brain with about 85% accuracy. We are currently looking at a range of new blood tests that seem to be even better at detecting amyloid, and at even lower cost.

The prospect of new drugs that can clear amyloid from the brain provide even more reason to intensify efforts to identify amyloid pathology early, cheaply and at scale.

Studies using the whole NSHD cohort have also shown complex relationships between cognitive function and several bodily functions, including those of the lungs, bones and kidneys. This probably reflects biology shared between the brain and these organs. We are currently looking to see how these findings relate to the brain health measures we have made in Insight 46. A similar “common cause” story applies to depression and cognitive function, and we are currently looking into how depression relates to the brain.

On the other hand, health-related behaviour such as smoking, physical exercise and healthy diet genuinely seem to predict cognitive function (negatively for smoking, positively for exercise and diet).

We have been emphasising prediction of health problems, but it’s equally important to understand resilience. Why can some people navigate through or escape these problems altogether even though they are apparently at risk, from genes or certain disadvantages in life? Does it come down to pure luck? But luck is, of course, just another way of saying we don’t know something.