Heightened cognitive ability may be causally associated with lower inflammation

A post first published on the PsyPost blog interviewed IEU researcher Chloe Slaney about a new paper exploring associations between chronic low-grade systemic inflammation and cognitive function.

While there may be associations between chronic low-grade systemic inflammation (slightly elevated levels of inflammation markers measured in the blood) and cognitive function, a new study suggests that the evidence for a causal relationship is limited. The research, which appears in Brain, Behavior, and Immunity, suggests that low-grade systemic inflammation doesn’t cause reduced cognitive function. Surprisingly, however, the findings provide preliminary evidence that greater cognitive ability leads to decreased inflammation.

Cognitive function has been shown to predict important life outcomes such as educational attainment, occupation status, health-related mortality, and quality of life. Cognitive dysfunction is also a key feature of various mental health disorders and physical illnesses, making it a significant clinical concern. Despite its importance, there are limited effective treatments for cognitive dysfunction.

“Cognitive impairment (deficits in mental activities such as attention and memory) is a common and often overlooked feature of many medical conditions, for which there are few treatment options available,” said study author Chloe Slaney, a senior research associate at the Immunopsychiatry Programme at the University of Bristol.

“Studies have shown a link between chronic low-grade systemic inflammation (slightly elevated levels of proteins in the blood which are present despite no evidence of injury or infection) and poorer cognition. However, it is not clear whether this relationship is causal.”

“That is, it is not clear whether inflammation negatively affects cognition, or if poorer cognition leads to increased inflammation, or whether both are an effect of other causes,” Slaney told PsyPost. “We were interested in this topic because we want to understand whether inflammation could be a valid target to prevent and treat cognitive impairment.”

A large-scale study to examine associations

The researchers aimed to fill these gaps in the literature by conducting a large-scale study using a population-based cohort to examine the associations between inflammatory markers and cognitive function. They also employed Mendelian randomization, a genetic epidemiological method, to explore potential causal relationships between inflammation and cognition.

Slaney and her colleagues used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), which is a large population-based birth cohort that initially recruited pregnant women in the United Kingdom with expected delivery dates between April 1991 and December 1992.

The cohort includes information on genetics along with mental and physical health. When the participants reached age 24, the researchers measured markers of inflammation in their blood samples and assessed their cognitive abilities.

The researchers found limited evidence of an association between C-reactive protein (CRP), a marker of inflammation, and cognitive measures.

On the other hand, they found that another inflammation marker called GlycA was associated with poorer working memory, emotion recognition, and response inhibition at age 24. But these associations disappeared after adjusting for potential confounding factors.

Similarly, interleukin-6 (IL-6), another inflammatory marker, was also associated with poorer working memory, emotion recognition, and response inhibition, but these associations did not persist after adjusting for confounders.

In addition, in the genetic analyses, the researchers did not find strong evidence for an effect of inflammation markers on cognitive measures at age 24. Similarly, there was not strong evidence for a causal effect of cognition on inflammatory markers.

“Our findings suggest that in young people low-grade systemic inflammation does not seem to have a noticeable effect on emotion recognition, impulsivity, and working memory,” Slaney told PsyPost. “Instead, links between inflammation and these cognitive domains could be due to other factors which may impact them both (e.g., BMI, smoking). This is important because it suggests that inflammation may not be an effective treatment target for impairments in these domains in young adults.”

“It also highlights the need for more studies to investigate whether inflammation affects cognition and for whom (i.e., whether there are sub-groups of individuals for whom inflammation may affect cognition), which in turn may inform future clinical trials.”

“As previous studies have reported associations between inflammation and cognition, I was surprised that we did not see a noticeable effect of low-grade inflammation on the cognitive domains examined here,” Slaney said.

However, across a broader age range, there was some evidence that higher general cognitive ability may be causally related to lower levels of CRP, IL-6, and GlycA.

“Our findings also suggest that low-grade systemic inflammation does not have a noticeable effect on general cognitive ability,” Slaney explained. “However, we did find evidence that higher general cognitive ability decreases inflammation. It is not clear why this could be the case; one possibility is that people with higher general cognitive ability may engage more in lifestyle factors that reduce inflammation (e.g., increased physical activity, not smoking). However, we need to do further work to better understand this relationship.”

But the researchers said that the sample size of their study might not have been large enough to reliably detect statistically significant associations.

“A major caveat of our study is its small sample size – of around 3,000 people – when testing causal relationships between inflammation and specific cognitive domains,” Slaney explained. “More work is needed in larger samples before strong conclusions can be drawn; we are currently investigating this in a larger cohort in the Netherlands which will include data on around 90,000 individuals.”

“Another caveat is that the immune system is complex and involves lots of proteins and cells, here we just focused on a few (Interleukin-6, C-reactive protein, Glycoprotein Acetyls). Further studies are needed to explore the role of other proteins and immune cells on cognition.”

Important questions still need to be answered

To find out if inflammation could be an effective target for improving cognitive problems, Slaney said there are still three important questions that need to be answered:

“1) Does the relationship between inflammation and cognition differ by age (i.e., are there ‘sensitive periods’ when inflammation may influence cognition) or other sub-groups (e.g., people with specific medical conditions)?

2) Does inflammation localised in the brain affect cognition?

3) Does inflammation affect other cognitive domains (e.g., decision-making, attention, processing positive vs negative stimuli)?”

The study, “Association between inflammation and cognition: Triangulation of evidence using a population-based cohort and Mendelian randomization analyses“, was authored by Chloe Slaney, Hannah M. Sallis, Hannah J. Jones, Christina Dardani, Charge Inflammation Working Group 1, Kate Tilling, Marcus R. Munafò, George Davey Smith, Liam Mahedy, and Golam M. Khandaker.

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