From womb to midlife: Prenatal immune disruptions reshape memory and cognitive aging

New research reveals how prenatal inflammation affects brain circuits and the immune system and shapes cognitive health decades later – revealing clues to aging and disease resilience.

Research: The prenatal immune origins of brain aging differ by gender. Image credits: Shutterstock AI

This is evident from a recent study published in the journal Molecular psychiatrya team led by researchers at Harvard Medical School examined how prenatal exposure to maternal pro-inflammatory cytokines affected memory-related brain circuits and immune functions in offspring over the course of 50 years.

The study examined sex-specific differences in brain activity and memory performance and linked disruptions in the fetus’s immune system to long-term health effects, particularly cognitive and immune resilience in middle age.

Background

The aging population worldwide faces significant challenges related to memory loss and cognitive diseases such as dementia and Alzheimer’s disease.

Research suggests that differences in memory performance between men and women vary with age and hormonal changes, with women often showing better verbal memory until menopause.

Furthermore, early life factors such as prenatal conditions are increasingly recognized as critical to long-term cognitive health.

Research has shown that maternal immune activation during pregnancy, caused by factors such as inflammation, alters fetal development and can affect memory circuits.

Animal model studies have revealed the mechanisms by which maternal inflammation disrupts neural processes crucial for memory. Although cognitive and immune dysfunctions associated with maternal immune problems during pregnancy have been observed in children and young adults, their persistence into old age and the role of sex-specific brain and immune responses remain unclear.

Furthermore, research links increased inflammasome activity, a marker of immune dysregulation, to Alzheimer’s pathology, which could have implications for understanding age-related memory decline.

About the study

The current study examined the long-term effects of prenatal maternal immune activity on memory and immune functions in offspring.

The researchers used data from a prenatal cohort recruited between 1959 and 1966 and focused on 204 participants who were equally divided by sex and were approximately 50 years old.

Maternal serum samples collected from the prenatal cohort during the late second or early third trimester were analyzed for pro-inflammatory cytokines, specifically interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), given their role in brain development . The researchers also measured the anti-inflammatory cytokine IL-10, but found that this had no significant effect, highlighting the specificity of pro-inflammatory cytokines.

Participants were categorized based on their prenatal exposure levels.

The adult offspring underwent clinical evaluations, neuropsychological testing, and functional brain imaging. Their memory performance was assessed using tasks such as the Face-Name Associative Memory Exam and the Selective Reminding Test.

Furthermore, brain activity and connectivity during memory encoding were evaluated using functional magnetic resonance imaging (MRI), with a focus on regions such as the hippocampus and ventrolateral prefrontal cortex.

The researchers also conducted sex-specific analyzes to assess interactions between maternal cytokine exposure and brain activity, controlling for socioeconomic and demographic factors.

Reproductive history and hormonal assessments of the female participants were used to categorize them based on reproductive stages, allowing examination of postmenopausal effects.

Furthermore, the immune function of midlife offspring was evaluated using markers such as the NLRP3 inflammasome score. NLRP3 or nucleotide binding and oligomerization domain (NOD), leucine-rich repeat (LRR), and pyrin domain-containing protein 3 is a protein linked to inflammatory responses to toxins, injury, or antigens.

Results

The results indicated that prenatal exposure to maternal pro-inflammatory cytokines had sex-specific long-term effects on immune function and memory circuitry in the offspring.

Increased maternal IL-6 and TNF-α levels were associated with impaired performance on memory tasks and altered brain activity, especially in the hippocampus and ventrolateral prefrontal cortex, in male offspring. These effects were associated with poorer task-evoked brain responses during memory encoding and reduced functional activity.

In women, the effects of prenatal exposure emerged after menopause, with higher levels of maternal cytokines correlating with reduced memory performance and altered connectivity between memory-related brain regions.

Interestingly, no significant associations were observed in pre- or perimenopausal women, suggesting that reproductive aging amplifies these effects.

Furthermore, the study identified changes in immune function in middle age. Increased prenatal exposure to cytokines was associated with increased inflammasome activity in the offspring, especially in postmenopausal female offspring, indicating a preserved hyperimmune state. This increased immune response is also linked to poorer episodic memory performance.

Furthermore, children’s standardized academic performance at age seven was linked to adults’ memory outcomes, suggesting the predictive value of early cognitive indicators for lifelong cognitive health. This highlights the role of prenatal conditions in shaping cognitive trajectories in the short but also long term.

In contrast to the pronounced effects of IL-6 and TNF-α, no significant effects were observed for IL-10, underscoring the critical influence of pro-inflammatory cytokines on memory and immune outcomes.

Conclusions

Overall, the results suggested that prenatal exposure to maternal inflammatory cytokines had a lasting impact on memory and immune functions in offspring, with clear sex-specific effects emerging across the lifespan. Male offspring were more likely to show deficits, while the effects were enhanced after menopause in women.

These findings reported the role of early immune perturbations in shaping lifelong cognitive and immune resilience and highlighted the need for targeted interventions to reduce the risks associated with prenatal inflammatory exposure. Although the study is comprehensive, the authors acknowledge limitations, including the focus on a single time point for cytokine measurement and sample size limitations for some analyses.

These findings provide a basis for future research into the link between prenatal immune activity and aging-related conditions such as Alzheimer’s disease.