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expert reaction to biomarkers for inflammation in middle-age predicting cognitive impairment in later life

In a new study, published in Neurology, scientists suggest the people who have biomarkers tied to inflammation in their blood in their 50s and 60s may have more brain shrinkage decades later than people without the biomarkers.


Dr Jennifer Pocock, Senior Lecturer in the Department of Neuroinflammation, Institute of Neurology, UCL, said:

“Whilst the actual methodology of this study is not my research expertise, I think the conclusions and caveats of the findings are reasonable. I am not sure it yet provides solid evidence that peripheral inflammation causes brain shrinkage as the researchers did not measure inflammation before brain shrinkage, so it is not clear which way round these changes occurred. However the authors themselves have been careful not to jump to this conclusion and have stated that it is an association in their paper title.”


Prof Sir Peter Lachmann, Emeritus Professor of Immunology, University of Cambridge, said:

“This paper makes an interesting contribution in providing further evidence for the importance of inflammation in late life disease.

“It is well established that there is a ‘hyper-inflammatory phenotype’ based largely on genetic factors that is of value in protecting the young from bacterial infection before they have made IgG antibodies to the bacteria they encounter; but which, in later life predisposes to the inflammatory diseases of old age. These include age related macular degeneration and probably accelerated atherosclerosis and also probably CNS disease and dementia.

“The Atherosclerosis Risk in Communities Study (ARIC) on which this paper is based was started in 1989 which may account for the lack of any DNA based markers of the hyper inflammatory phenotype. There are also no markers related to complement which is the major predisposing inflammatory system for age-related macular degeneration. However, the neutrophil count is a robust indicator and it was shown in the EPIC Norfolk study that a raised neutrophil count in healthy middle-aged subjects was a predictor of earlier death.

“The present findings would support the views that anti-inflammatory medicines such as aspirin and avoidance of smoking (which enhances neutrophil activation) might delay the onset of dementia. “


Dr Joe Butchart, Honorary Clinical Senior Lecturer, University of Exeter Medical School, said:

“This is an important study which lends support to the hypothesis that the immune system plays a role in the development of dementias such as Alzheimer’s disease. Previous research has shown that anti-inflammatory medications, taken for other reasons, may reduce the risk of Alzheimer’s disease. Other research has shown that cognitive symptoms progress more rapidly in people living with dementia when they suffer inflammatory episodes, like chest and urine infections. This is one of the first studies to show that inflammation in midlife may affect cognitive decline and brain atrophy many years later.

“The authors are careful to point out that we cannot be sure whether inflammation is causing the cognitive problems later on, or whether inflammation is actually a response to very early cognitive change in midlife. In either case, this work suggests that the seeds of cognitive problems later on in life are already planted during middle age. We already understand that midlife problems with high blood pressure, high cholesterol and diabetes all contribute to the risk of dementia later on in life.

“This research suggests that we must now add high systemic inflammation to this list of risk factors. Overall, there is a growing consensus that, in the future, we may be able to prevent dementias like Alzheimer’s disease if we begin addressing risk factors such as these during middle age.”


Dr Carol Routledge Director of Research at Alzheimer’s Research UK, said:

“There is growing evidence that inflammation plays an important role in the development of Alzheimer’s disease. This large, well-conducted study suggests a link between inflammation and brain changes related to Alzheimer’s, but it didn’t investigate whether participants actually went on to develop the disease.

“We know that processes involved in damaging the brain in a disease like Alzheimer’s can start many years before changes become apparent on brain scans or people experience any symptoms. This research points to inflammation as a potential early indicator of later brain degeneration, but we cannot say whether inflammation could be causing brain shrinkage or if it is a response to other damaging processes that might already be underway.

“The researchers measured levels of inflammation at a single point in time and we don’t know whether this gives a reliable indication of inflammation more generally. As the participants only had brain scans at the end of the study it is impossible to rule out differences in brain size existing before the researchers measured levels of inflammation. Future research will need to measure changes over time to piece together more clearly how inflammation fits in to the timeline of changes involved in Alzheimer’s disease. Alzheimer’s Research UK is currently funded several promising early drug discovery programmes focused on inflammation in Alzheimer’s and it is an important area of ongoing research.

“Finding the optimal time points for interventions that could tackle diseases like Alzheimer’s is essential if we are to limit the growing impact these conditions have. Midlife is emerging as critical point for taking steps to promote brain health. Current evidence suggests that not smoking, keeping blood pressure and cholesterol in check, eating a balanced diet, drinking in moderation and staying mentally and physically active can all help to maintain a healthy brain as we age.”


Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, said:

“Inflammation and problems with the immune system are increasingly thought to play a role in the development of dementia.

“This study suggests a link between increased inflammation in middle-aged people and shrinkage in areas of the brain that are known to be affected by Alzheimer’s disease. However, this study was looking only at brain shrinkage and did not look directly at the development of Alzheimer’s disease, or other types of dementia. Although these results are a helpful addition to the wider body of research around brain health and inflammation, what we need is more research to further clarify this relationship.

“While the study may not conclusively show that brain shrinkage is due to inflammation, it does highlight the importance of taking care of your cognitive health throughout your life, particularly in middle age. This includes eating a healthy balanced diet, taking regular exercise and managing conditions like diabetes and high blood pressure.”


* ‘Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study’ by Walker et al. published in Neurology on Wednesday 1st November.


Declared interests

Dr Pocock: “I am employed by UCL and have grant funding from PHAGO EUR, Eisai/UCL, and BBSRC, and am a member of the American Society for Neuroscience and the Alzheimer’s Society UK. No other conflicts of interest.”

Prof. Lachmann: “I have studied  down regulation of the complement system as a therapeutic strategy for many years. I do not believe that I have a conflict of interest with regard to this work.”

Dr Butchart: “I have received research funding from Pfizer Inc. for a study of anti-inflammatory treatment in Alzheimer’s disease.”

Dr Routledge: “No interests to declare.”

None declared

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