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Mid-life inflammation linked to late-life Alzheimer’s


US study finds possible tie between immune system responses and neurodegeneration. Paul Biegler reports.


An MRI image of a patient with Alzheimer's disease. Is the condition linked to inflammation decades earlier?
An MRI image of a patient with Alzheimer's disease. Is the condition linked to inflammation decades earlier?
BSIP/UIG via Getty Images

While shrunken heads are the province of faraway tribes and distant times, shrunken brains happen to be an unfortunate fact of everyday life. The normal brain shrinks significantly with age, some regions by as much as 25% before the age of 80.

New research, however, published in the journal Neurology, finds that inflammation in middle life may be exacerbating not just brain shrinkage with age, but also contributing to a doddery memory.

The study, led by Keenan Walker from the Department of Neurology at Johns Hopkins University School of Medicine in the US, analysed data from the Atherosclerosis Risk in Communities (ARIC) study. ARIC began in 1987, recruiting participants from Maryland, Minnesota, North Carolina and Mississippi.

Between 1987 and 1989, 15,792 middle-aged adults were assessed for baseline levels of a range of inflammation markers, including white blood cell count, and clotting proteins called fibrinogen and Von Willebrand factor.

Twenty-four years later, between 2011 and 2013, a cohort of 1,633 of the original participants had MRI brain scans. They also underwent memory testing using the delayed word recall test, which asks subjects to memorise 10 words and repeat them a short time later.

The researchers found that higher inflammation scores on the baseline tests were associated with reduced size of various brain regions showing up on MRI.

Those regions included the occipital lobe, the hippocampus and the so-called “Alzheimer Disease signature”, a constellation of brain areas whose smaller size has been linked to the neurodegenerative disease.

Specifically, participants with elevations in three or more of the inflammatory biomarkers had, on average, 5.7% smaller occipital lobes, 4.6% smaller hippocampal volumes and 5.3% smaller Alzheimer Disease signature regions.

Inflammation was also associated with poorer performance on the memory test. Those with normal markers at baseline recalled, on average, just under 5.5 words, while those with three or more elevated markers recalled five.

As the researchers note, there is already an established link between systemic inflammation – low grade activation of a range of immune proteins that fight infection and respond to injury – and increased brain atrophy with age.

The devil, as always, is proving causation.

The authors concede that inflammation could simply be a response to another disease process affecting the brain, which subsequently shifts biomarkers in the peripheral blood.

But they also note their study, traversing nearly a quarter of a century, has advantages over others, such as the Framingham Heart study, which collected “cross-sectional” data at a single point in time on both inflammation and brain size.

“The current findings provide support for a potential causal, rather than associative, role of systemic inflammation in late-life neurodegeneration (i.e., atrophy) and resulting cognitive decline,” the researchers write.

Commenting on the study, Professor of Neuropsychiatry at Australia’s University of New South Wales, Perminder Sachdev, said it, “further supports the possibility that a state of high inflammation through life may be deleterious to the brain.”

But Sachdev also counselled caution in interpreting the findings, noting that both brain volumes and memory were tested once and so couldn’t show a decline, and that inflammatory markers, also measured only once, often alter temporarily with illness and infection, a potential confounding factor.

“While interesting, this study leaves many questions unanswered,” he said.

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Paul Biegler is a philosopher, physician and Adjunct Research Fellow in Bioethics at Monash University. He received the 2012 Australasian Association of Philosophy Media Prize and his book The Ethical Treatment of Depression (MIT Press 2011) won the Australian Museum Eureka Prize for Research in Ethics.
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