Summary: Maternal immune activity during pregnancy influences memory circuitry in offspring, with sex-specific effects extending into midlife. Elevated immune markers like IL-6 and TNF-a in mothers were linked to adverse brain activity in memory regions, particularly in postmenopausal women, and lower cognitive performance in children.
These findings suggest that prenatal immune environments may predispose offspring to memory disorders like Alzheimer’s disease later in life. Researchers emphasize that the brain’s adaptability offers opportunities for early interventions to mitigate risks and promote resilience.
Key Facts:
- Prenatal exposure to high maternal immune activity impacts memory brain regions in offspring, with distinct effects in males and females.
- Postmenopausal women exposed to high prenatal immune markers showed heightened proinflammatory states and adverse memory circuitry activity.
- Evidence links prenatal immune exposure to lower cognitive performance as early as age seven, suggesting a lifelong impact on brain health.
Source: Brigham and Women’s Hospital
An estimated 13.8 million people in the U.S. will have Alzheimer’s disease (AD) by 2050, two thirds of whom are projected to be women. The brain circuitry underlying memory is widely known to differ based on biological sex, but sex-based drivers of aging and AD are still unclear.
A study by investigators from Mass General Brigham analyzed data from participants who have been followed for over 50 years, starting before their births.
Researchers found that maternal immune activity during a critical period of sex-dependent brain development in pregnancy affected the offspring’s long-term memory circuitry and function in childhood and midlife, with different patterns for males and females.
Findings are published in Molecular Psychiatry in a paper titled “Prenatal immune origins of brain aging differ by sex.”
“Brain aging is also about brain development, and understanding sex differences in brain development is critical to understanding sex differences in the aging brain,” said corresponding author Jill M. Goldstein, Ph.D., MPH, founder and executive director of the Innovation Center on Sex Differences in Medicine of Massachusetts General Hospital, and Professor of Psychiatry and Medicine at Harvard Medical School.
“This paper is a first step toward looking at the fetal origins of Alzheimer’s disease, which, like many chronic diseases, develops across the lifespan and is influenced by early development in a way we might not ordinarily consider.”
This study was based on findings from a cohort established over 60 years ago, which included the adult offspring of nearly 18,000 pregnancies between 1959 and 1966, followed as part of the New England Family Study (NEFS).
The present investigation comprised 204 individuals born during the study who were or were not exposed to an adverse in utero immune environment (i.e., elevated levels of immune markers, such as cytokines IL-6 and TNF-a) and followed into midlife 50 years later.
The team used functional brain imaging to examine the impact of this early exposure on brain regions in the memory circuitry that are dense in these cytokine receptors and sex hormone receptors and exhibit sex differences in development and functioning beginning in fetal development.
The researchers found that elevated levels of IL-6 and TNF-a in mothers during pregnancy were linked with sex differences in adverse brain activity in memory circuitry in the offspring later in life, particularly in postmenopausal women.
These women also expressed higher markers of a proinflammatory state in midlife. Further, researchers saw evidence of the impact of these immune markers even earlier, in children’s cognitive performance at age seven, underscoring the link between exposures during pregnancy and brain health later in life.
Their findings suggest that elevated maternal prenatal immune activity may contribute to the development of heightened immune and stress sensitivity in the offspring, which, the researchers hypothesized, may predispose them to memory disorders, like AD, later in life, in sex-dependent ways.
As participants age, the researchers are continuing to follow them to examine amyloid levels and other measures of AD-related pathology to further explore the association between prenatal immunity and AD.
Ongoing goals include understanding the mechanisms by which maternal immune activity influences fetal brain development, identifying biomarkers for future memory dysfunction in early midlife, and understanding how other periods of development, such as puberty, influence the aging brain.
“While prenatal immune activity may affect brain development in the offspring, that does not mean pregnancy is deterministic,” Goldstein said.
“Of course, subsequent environmental exposures are key, just as in utero environment is important.
“Fortunately, the brain is exceptionally adaptable, and we want to understand the cognitive, behavioral, and sex-dependent factors associated with both risk and resilience in order to intervene early and maintain intact memory function as we age.”
About this inflammation, genetics, and Alzheimer’s disease research news
Author: Jill M. Goldstein
Source: Brigham and Women’s Hospital
Contact: Jill M. Goldstein – Brigham and Women’s Hospital
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Prenatal immune origins of brain aging differ by sex” by Jill M. Goldstein et al. Molecular Psychiatry
Abstract
Prenatal immune origins of brain aging differ by sex
With an increasing aging population and Alzheimer’s disease tsunami, it is critical to identify early antecedents of brain aging to target for intervention and prevention. Women and men develop and age differently, thus using a sex differences lens can contribute to identification of early risk biomarkers and resilience.
There is growing evidence for fetal antecedents to adult memory impairments, potentially through disruption of maternal prenatal immune pathways.
Here, we hypothesized that in utero exposure to maternal pro-inflammatory cytokines will have sex-dependent effects on specific brain circuitry regulating offspring’s memory and immune function that will be retained across the lifespan.
Using a unique prenatal cohort, we tested this in 204 adult offspring, equally divided by sex, who were exposed/unexposed to an adverse in utero maternal immune environment and followed into early midlife (~age 50).
Functional magnetic resonance imaging results showed exposure to pro-inflammatory cytokines in utero (i.e., higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in brain activity and connectivity underlying memory circuitry and performance and with a hyperimmune state, 50 years later.
In contrast, the anti-inflammatory cytokine, IL-10 alone, was not significantly associated with memory circuitry in midlife. Predictive validity of prenatal exposure was underscored by significant associations with age 7 academic achievement, also associated with age 50 memory performance.
Results uniquely demonstrated that adverse levels of maternal in utero pro-inflammatory cytokines during a critical period of the sexual differentiation of the brain produced long-lasting effects on immune function and memory circuitry/function from childhood to midlife that were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent.
