A large study in the Netherlands has found that inflammation is consistently linked to symptoms of depression and anxiety, as well as subtle impairments in cognitive function—particularly memory and attention. The researchers used both observational and genetic approaches to better understand whether these associations might be causal. While most associations were small, the results offer compelling support for the idea that chronic low-grade inflammation can influence emotional well-being and mental performance. The findings were published in the journal Translational Psychiatry.
Depression is one of the most common and disabling mental health conditions worldwide. It is often accompanied by problems with memory, attention, and decision-making. These cognitive issues are not just minor symptoms—they contribute to long-term disability and reduced quality of life. However, current treatments for depression and cognitive symptoms are often only modestly effective.
One hypothesis gaining traction is that inflammation, particularly low-level systemic inflammation, may underlie some cases of depression and related cognitive problems. Inflammation is the body’s natural response to infection or injury, but when it becomes chronic, it can begin to interfere with brain function. Previous studies have shown that people with depression tend to have higher levels of inflammatory proteins like interleukin-6 and C-reactive protein in their blood. But whether these proteins cause depression or are simply a byproduct of poor health is not yet settled.
“There is growing evidence that some individuals develop depression because of underlying immune dysfunction. Evaluating this scientifically is hard because there are many factors that are associated with both depression and immune dysfunction (substance use, poor diet, stress, adiposity), which makes disentangling causal relationships challenging,” said study author Naoise Mac Giollabhui, an assistant professor and clinical psychologist at Massachusetts General Hospital/Harvard Medical School.
“This paper was an opportunity to explore the association between inflammatory biomarkers and a range of mental health outcomes using a very large Dutch cohort study and to use an approach that would allow us to probe whether some specific immune biomarkers are causally linked with specific mental health outcomes.”
The study used data from the Lifelines cohort, a large, population-based study in the Netherlands that follows tens of thousands of individuals over time. More than 55,000 adults took part in the observational portion of the study, which examined levels of C-reactive protein in the blood, as well as symptoms of depression, anxiety, and performance on cognitive tests. Additionally, genetic data were available for over 57,000 participants, allowing the researchers to calculate genetic scores linked to several inflammatory markers, including interleukin-6, its receptor, and a compound known as GlycA.
The researchers first examined whether levels of C-reactive protein were associated with mental health symptoms and cognitive functioning. They found that higher levels of this immune marker were linked to an increased likelihood of depression, lower positive affect, higher negative affect, and slightly worse performance on tasks measuring executive functioning, attention, and psychomotor speed. These associations were statistically significant even after adjusting for important factors like age, body mass index, and existing health conditions, although the size of the effects was relatively small.
Next, the team looked at whether individuals with a genetic predisposition to higher inflammation also showed greater risk for mental health symptoms. They calculated genetic risk scores based on known variants that influence inflammation-related proteins. Here, they found that individuals with a higher genetic tendency toward elevated C-reactive protein or GlycA were more likely to experience negative affect and, in some cases, to meet criteria for depression or anxiety disorders. For example, the genetic score related to C-reactive protein was associated with a higher risk of anxiety, while the score for GlycA was tied to a higher risk of major depressive disorder.
Interestingly, most of the genetic risk scores were not linked to cognitive outcomes, with one exception. Individuals with genetic variants associated with higher levels of soluble interleukin-6 receptor—a key component of the immune system’s signaling pathways—showed slightly poorer memory performance. This finding suggests a possible role for specific inflammatory pathways in memory function.
The third method the researchers used was Mendelian randomization, which helps infer whether a factor like inflammation could be causing certain outcomes rather than merely being correlated with them. This method leverages the random inheritance of genetic traits to minimize confounding variables. Using this approach, the researchers found some tentative evidence that elevated C-reactive protein might causally increase the risk for anxiety. However, the association was just short of statistical significance, suggesting the need for more studies to confirm this result.
One of the most consistent findings across all methods was the link between inflammation—especially C-reactive protein—and negative affect. This refers to a general tendency to experience unpleasant emotions like anger, sadness, or fear. The fact that both measured inflammation and genetic risk for inflammation were tied to negative affect adds weight to the idea that immune system activity may influence emotional states beyond traditional diagnostic categories like depression or anxiety.
While the results support the idea that inflammation contributes to psychological symptoms, the authors emphasize that the effects observed were small in size. They suggest that inflammation may play a role in a subset of individuals or in specific types of symptoms, such as anhedonia, fatigue, or irritability. These symptoms have been previously linked to immune system activity and may define a distinct subtype of depression with biological underpinnings.
The study also adds to a growing body of research suggesting that inflammatory pathways may be more important for understanding emotional well-being than for understanding cognitive performance. The limited associations between inflammation and cognitive test outcomes, especially in the genetic analyses, imply that any cognitive effects of inflammation may be more subtle or context-dependent. However, the one notable exception involving interleukin-6 signaling and memory highlights the need for more research into specific immune pathways and their cognitive effects.
“These findings found fairly consistent associations between an immune marker measured in blood and depression, anxiety, cognitive abilities, and negative affect,” Mac Giollabhui told PsyPost. “We also found some evidence that genetic predisposition towards higher levels of immune markers were related to depression, anxiety, memory, and negative affect, suggesting these associations may be causal.”
But as with any study, there are limitations. The sample was largely made up of individuals of European descent, which may limit how broadly the results can be applied. “More work is needed to determine whether these results generalize to other groups,” Mac Giollabhui said. “Second, the impact of genetics as operationalized in this study on our biomarkers was pretty modest in size and it’s hard to know whether larger increases in immune biomarkers might have a cumulative and potentially greater effect on the outcomes we were looking at.”
“Our study focused on associations in the general population, which overall showed small associations between immune markers and mental health outcomes. Future studies are needed to replicate these findings and to focus on specific sub-groups and life stages (e.g., older populations),” added co-author Chloe Slaney, a senior research associate at the University of Bristol.
Despite these limitations, the findings provide new evidence that inflammation may play a small but measurable role in shaping emotional experiences and mental health risk. Importantly, the consistency of results across different types of analyses strengthens confidence in the idea that immune activity contributes to certain psychological traits and symptoms.
“The long-term goal is to better understand the role that immune dysfunction plays in depression in order to identify treatment targets,” Mac Giollabhui explained. “I am currently running a mechanistic clinical trial that examines whether experimental inhibition of immune signaling in depressed individuals with high levels of inflammation leads to change in mood and cognition as well as the underlying immune-based mechanisms. There are a lot of investigators world-wide who are currently working on this bigger question. I hope that we can harness this information to develop new and more effective treatments.”
The study, “Role of inflammation in depressive and anxiety disorders, affect, and cognition: genetic and non-genetic findings in the lifelines cohort study,” was authored by Naoise Mac Giollabhui, Chloe Slaney, Gibran Hemani, Éimear M. Foley, Peter J. van der Most, Ilja M. Nolte, Harold Snieder, George Davey Smith, Golam M. Khandaker, and Catharina A. Hartman.
