A major Dutch study has found consistent links between inflammation and symptoms of depression, anxiety, and mild cognitive impairments such as memory and attention issues. Using both observational and genetic methods, researchers aimed to determine whether these associations may be causal. While the effects were generally small, the findings offer compelling support for the idea that chronic low-grade inflammation may influence emotional well-being and mental functioning. The study was published in the journal Translational Psychiatry.
Depression remains one of the most prevalent and disabling mental disorders worldwide. Often accompanied by cognitive impairments—including problems with memory, concentration, and decision-making—these symptoms can significantly reduce quality of life and long-term functioning. Yet, existing treatments frequently fall short in addressing cognitive aspects of the disorder.
A growing hypothesis is that inflammation, particularly low-level systemic inflammation, could be a contributing factor to depression and related cognitive difficulties. Although inflammation is the body’s natural response to infection or injury, when it becomes chronic, it may begin to interfere with brain function. Previous studies have shown elevated levels of inflammatory proteins such as interleukin-6 and C-reactive protein (CRP) in people with depression. However, it remains unclear whether these proteins play a causal role or are simply byproducts of poor health.
“There’s increasing evidence that for some individuals, depression is driven by underlying immune dysfunction,” said study author Dr. Naoise Mac Giollabhui, a clinical psychologist and assistant professor at Massachusetts General Hospital and Harvard Medical School. “It’s scientifically challenging to assess this because both depression and immune dysfunction are associated with many overlapping factors—substance use, poor diet, stress, obesity—making it hard to untangle causality.”
“This paper provided an opportunity to leverage a large Dutch cohort to examine associations between immune biomarkers and a wide range of mental health outcomes, and to explore whether certain immune markers may be causally related to specific psychological symptoms,” Mac Giollabhui explained.
The study drew on data from the Lifelines cohort, a large-scale population study in the Netherlands that has tracked tens of thousands of individuals over time. More than 55,000 adults were included in the observational part of the study, which assessed CRP levels in the blood alongside symptoms of depression and anxiety and cognitive test performance. The researchers also had access to genetic data from over 57,000 participants, allowing them to calculate genetic scores associated with inflammatory markers, including interleukin-6 (IL-6), its receptor, and a compound called GlycA.
The researchers first examined whether CRP levels were linked to mental health symptoms and cognitive function. Elevated CRP was associated with increased risk of depression, more negative emotions, lower positive emotions, and slightly worse performance on tasks measuring executive function, attention, and psychomotor speed. These associations remained statistically significant even after adjusting for age, body mass index, and overall health status—although the effect sizes were small.
Next, the team explored whether individuals genetically predisposed to higher inflammation were also more likely to experience mental health symptoms. Using known genetic variations that affect inflammatory proteins, they found that individuals with a higher genetic tendency toward elevated CRP or GlycA were more likely to experience negative emotional states and, in some cases, meet clinical criteria for depression or anxiety. For example, genetic scores linked to CRP were associated with greater risk of anxiety, while GlycA-related scores were tied to increased risk of major depressive disorder.
Interestingly, most of these genetic scores were not linked to cognitive outcomes, with one exception: individuals with a genetic profile associated with higher levels of the soluble IL-6 receptor showed slightly poorer memory performance. This finding suggests that specific inflammatory pathways may play a role in memory function.
To further investigate causality, the researchers employed Mendelian randomization, a method that uses genetic variation to minimize confounding and estimate causal relationships. Through this technique, they found preliminary evidence suggesting that higher CRP levels may causally contribute to increased anxiety risk. However, this link was not strong enough to be considered definitive, indicating the need for further study.
One of the study’s most consistent findings was the relationship between inflammation—particularly CRP—and negative emotional states. These emotions, which include feelings such as sadness, anger, and fear, were consistently associated with both measured and genetically predicted levels of inflammation. This supports the idea that immune system activity may influence emotional states beyond traditional diagnostic categories like depression or anxiety.
While the findings support the hypothesis that inflammation can contribute to psychological symptoms, the authors emphasized that the overall effects were modest. They suggest that inflammation may be relevant in certain individuals or specific symptom profiles—such as anhedonia, fatigue, or irritability—which have previously been linked to immune system activity and may define a biologically distinct subtype of depression.
The study also contributes to a growing body of evidence suggesting that inflammation may be more crucial for understanding emotional health than cognitive performance. The limited links between inflammation and cognitive test outcomes—especially in genetic analyses—suggest that its cognitive effects may be subtle or context-dependent. Nonetheless, the observed link between IL-6 signaling and memory performance highlights the need for more targeted research into specific immune pathways and their cognitive implications.
“These findings show fairly consistent associations between immune markers measured in the blood and depression, anxiety, cognitive ability, and negative emotionality,” Mac Giollabhui told PsyPost. “We also found some evidence that genetically elevated immune markers are associated with these same outcomes, suggesting that some of these links may be causal.”
As with any study, there are limitations. The sample was predominantly of European descent, which may limit the generalizability of the findings. “Further research is needed to determine whether these results hold in other populations,” Mac Giollabhui noted. “Also, the genetic influences on our biomarkers were relatively modest, so it’s unclear whether more pronounced increases in these markers would produce larger or cumulative effects.”
“Our study focuses on associations in the general population, where the links between immune markers and mental health outcomes are small overall,” added co-author Dr. Chloe Slaney, a senior research associate at the University of Bristol. “Future research should replicate these findings and explore specific subgroups and life stages, such as older adults.”
Despite these limitations, the study provides new evidence that inflammation may play a subtle but measurable role in shaping emotional experience and mental health risk. The consistency of findings across different analytic methods strengthens confidence in the idea that immune system activity is meaningfully related to certain psychological traits and symptoms.
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