Focus on stroke: The tangled knot of dementia and stroke

For decades, stroke and dementia were treated quite separately in the UK, both clinically and in research, despite both being diseases of the brain. Dementia – especially Alzheimer’s disease – had been claimed by the psychiatrists and neurologists, while stroke remained in general medicine or geriatrics.

Today, scientists and doctors are becoming ever more aware of the links between stroke and dementia. The same risk factors apply to both diseases, implying some degree of common mechanism in their development. Michael Regnier asks Professor Rob Stewart whether stroke and dementia could be different manifestations of the same underlying disease.

A cast of blood vessels in the brain, currently on display in Wellcome Collection’s Brains exhibition. Credit: Gordon Museum, King’s College London

“Anyone with any vascular risk factor – higher blood pressure, diabetes, higher cholesterol and so on – is also at risk of Alzheimer’s,” says Professor Rob Stewart, an old-age psychiatrist based at the Institute of Psychiatry, King’s College London.

Stewart has a long-standing research interest in dementia and its relationship to cardiovascular disease. One of his current projects is SABRE-COG, an extension of the SABRE study described in ‘Predicting and preventing stroke’ earlier in this series. He is taking advantage of the same cohort to assess the effects of cardiovascular risk factors on cognitive skills and other potential early indicators of dementia.

“It is allowing us to see how all the various risk factors exert their effects, and in different ways in different ethnic populations,” he says. “Using three different ethnic groups and their distinct profiles of risk factors, we’ll get a better picture of how these factors come together to cause disease.”

Data from SABRE spans twenty years but because dementia more commonly develops in old age, not many of the participants will have been diagnosed with dementia, which is why SABRE-COG is monitoring early signs of cognitive difficulties. According to Stewart, this is a common problem in longitudinal studies of dementia, and it makes it challenging to prove the contribution of vascular risk factors to dementia or, conversely, to show that treating factors like blood pressure and cholesterol has a preventive effect as it does in stroke and heart disease. “Dementia comes quite far down the line, which makes it difficult and possibly impossible to get clear trial evidence that preventive measures stop dementia.

“Observational information shows these factors are associated with dementia risk but it’s fairly unlikely there will be a major trial to show lowering blood pressure prevents dementia because we know it’s good for you anyway.” It may be that trials in specific groups – such as stroke survivors – will be done to see if treating vascular disease prevents dementia, but in terms of general public health messages, the observational information is all we have to go on.

Nevertheless, says Stewart, “Vascular risk factors are the most important environmental risk factor for dementia as a whole because they are very common and potentially reversible. We know people with cardiovascular disease are more likely to develop dementia; we should do more to prevent it. Keep blood pressure down, prevent diabetes or make sure it’s well treated, keep cholesterol down, eat healthily, keep physically active. All the same messages as for cardiovascular disease but adding in a layer of importance by including dementia.”

‘Ageing with Grace’

In the 1990s, a landmark US study began to show the power of the interplay between vascular disease and dementia. The Nun Study has followed several hundred School Sisters of Notre Dame, who were originally recruited by epidemiologist Dr David Snowdon. Remarkably, these nuns all agreed to donate their brains to the study after they died. When allied with information from mental and physical tests in life, the post-mortem findings allow the researchers to assess the connections between potential risk factors, signs of dementia and brain pathology.

In a book about the Nun Study, Snowdon wrote: “Strokes can bring on the sudden appearance of dementia symptoms that are caused by the rupture or blockage of a blood vessel. In contrast, the symptoms of Alzheimer’s disease usually progress slowly. However, with advancing age, these two diseases may become intertwined and confused. How stroke and Alzheimer’s knot together is far from an academic question. Effective prevention and treatment strategies might result from untying that knot.”

Because the nuns have lived very similar lives in the same environment, the degree of confounding by other factors is minimal. For example, none of them smoked and they all had essentially the same diet and lifestyle. Differences between those who developed dementia and those who didn’t can therefore be picked up more readily than in broader population studies.

The results were startling. In a 1997 paper published in the Journal of the American Medical Association, Snowdon and colleagues presented findings on the links between dementia in life, signs of vascular damage and the characteristic signs of Alzheimer’s disease – amyloid plaques and tau tangles – in the nuns’ brains.

Of those with the plaques and tangles of Alzheimer’s disease but no signs of stroke, 57 per cent had had dementia. But of those with both Alzheimer’s and stroke damage, the proportion with dementia was 93 per cent. “What we found,” wrote Snowdon, “went beyond loosening the knot of confusion regarding how Alzheimer’s disease and stroke interact – it challenged some of the most common diagnostic truisms.”

Stewart says there are two possible explanations for how vascular disease exacerbates the dementia caused by Alzheimer’s disease: “Vascular changes in the brain might be directly linked to amyloid plaques and tau tangles – there is some evidence for this in studies where animals with ischaemia in the brain seemed to produce more amyloid.

“Or, and there is more evidence for this, there are two parallel processes combining to cause dementia. Each causes damage to the brain and, as the damage accumulates, the resulting dementia becomes more severe.”

It is also possible that strokes impair the brain in such a way as to reveal undiagnosed dementia. Stewart explains that, in the early stages of Alzheimer’s disease, people can often compensate for signs of dementia such as memory loss for quite a long time. Compensating becomes much harder when the effects of vascular disease are causing problems in other brain functions as well.

Either way, vascular damage caused by strokes, whether detected in life or not, increased the nuns’ risk of dementia, and it was clear that the classic hallmarks of Alzheimer’s disease were not enough on their own to guarantee dementia.

Vascular dementia

In the UK, where dementia is treated by psychiatrists or neurologists while stroke falls within geriatrics or general medicine, the separation of stroke and dementia has been stark. Perhaps because of this, the immediate and specific cognitive effects that a stroke can have are often thought of as categorically different to the general degenerative decline of ‘classic’ dementia. However, many people experience cognitive difficulties after stroke that are equivalent to years of dementia.

Within the dementia field, patients who are known to have suffered strokes or have other signs of vascular disease are treated differently. “Alzheimer’s disease has tended to be clinically defined so as to exclude anyone with vascular damage,” says Stewart. “Under some definitions, if a patient has any level of stroke disease, they can’t have Alzheimer’s, they have ‘vascular dementia’.”

The distinction between these two types of dementia stems from studies in the 1960s and 1970s, which looked at the brains of people who had died with dementia. Some had tangles and plaques; others did not but showed vascular changes from lots of strokes. These results suggested two separate causes of dementia – Alzheimer’s disease or so-called vascular dementia – but, says Stewart, a lot has changed since then.

“An awful lot of dementia in those days was diagnosed in people in their sixties or seventies,” he explains. “Someone diagnosed at that age probably does have only one cause. Most people dying with dementia today, however, are in their eighties and nineties so while most of them have Alzheimer’s disease, nearly all of them will have some degree of vascular dementia in their brain as well.

“Trying to keep Alzheimer’s disease and vascular dementia separate is unrealistic. It looks good in a textbook but it fails to reflect reality – most people will have a mixture of the two and, in fact, lots of people diagnosed with vascular dementia show progression that is much more like Alzheimer’s disease.”

This matters now that treatments are being developed specifically for Alzheimer’s disease. “It is assumed these new treatments will work better in people with Alzheimer’s disease,” says Stewart. “But because someone who has been diagnosed with vascular dementia cannot, according to some definitions, have Alzheimer’s as well, there are people who may miss out on effective treatments for dementia resulting from unrecognised Alzheimer’s.”

Untangling the knot

Given that degenerative damage to the brain’s small blood vessels can cause vascular dementia as well as stroke, does dementia influence the risk of stroke in these small arteries? Could stroke and vascular dementia – if not all dementia – even be two possible outcomes of one underlying disease process?

The evidence to date is not clear about whether dementia increases the risk of stroke. However, there is a school of thought that implicates the amyloid plaques of Alzheimer’s disease in the development of small vessel vascular disease as well.

“The role of amyloid in blood vessels is intriguing,” says Stewart. “Amyloid is not only deposited around the nerve cells to form these plaques seen in Alzheimer’s disease, but also in the blood vessels.”

Could the build-up of amyloid be causing problems with the blood supply, just as fatty deposits in the arteries reduce blood flow and increase the risk of stroke? We still do not know exactly what role amyloid plays in the brain. It is possible that it is there as part of the brain’s natural response to vascular damage, which is the real root of disease. Or the amyloid may be causing more damage despite trying to repair the brain, much as inappropriate stimulation of the immune system causes autoimmune diseases.

New trials of drugs for Alzheimer’s disease will help to determine whether amyloid is the culprit or an innocent bystander. We will be able to see on brain scans if the trial drugs successfully remove amyloid. If it is the cause of dementia, removing amyloid should lead to improvements for the trial participants. It will be very interesting if the research shows any difference in the risk of small vessel stroke after the removal of amyloid as well.

Whatever the outcome of such trials, it seems that Snowdon’s “knot of confusion” will require a much greater understanding of the overlap between Alzheimer’s disease, vascular dementia and stroke. We cannot study them separately any longer. Psychiatrists like Stewart know this, as do a growing number of neurologists and stroke specialists. Greater collaboration between these disciplines is needed before we can untie the knot completely.

Notes and references

Snowdon, D. Aging with Grace: The Nun Study and the science of old age. London: Fourth Estate; 2001.

Snowdon, D., Greiner, L., Mortimer, J., Riley, K., Greiner, P., & Markesbery, W. (1997). Brain Infarction and the Clinical Expression of Alzheimer Disease: The Nun Study JAMA: The Journal of the American Medical Association, 277 (10), 813-817 DOI: 10.1001/jama.1997.03540340047031

UK Clinical Research Network information on SABRE-COG.

SABRE-COG is funded by the Wellcome Trust.

This article is part of the Wellcome Trust’s Focus on stroke, a series of articles, interviews and videos running throughout May 2012, which is the Stroke Association’s Action on Stroke Month.

For more information on stroke, visit the Stroke Association’s site or call its helpline on 0303 303 3100. If you or someone with you is suspected of having a stroke, call the emergency services immediately.