Given the increasing life expectancy and the rising prevalence of Alzheimer’s disease, it is crucial to understand how prenatal exposures may influence the risk of cognitive impairment decades later. The study reinforces that the impacts of inflammation during pregnancy may persist throughout life, affecting men and women differently.
Preserving memory as we age is one of the greatest global health challenges. It is estimated that by 2050, more than 20% of the United States population will be over 65 years old, and approximately 75% of older adults will experience memory-related difficulties.
In addition, approximately 13.8 million people will be diagnosed with Alzheimer’s disease (AD), two-thirds of whom will be women.
Interestingly, women perform better on verbal memory tests throughout life, but this advantage tends to diminish with the hormonal decline caused by reproductive aging. This reinforces the need to develop specific strategies that consider biological differences between the sexes to protect memory over time.
Factors that influence memory health can begin as early as fetal development. Studies indicate that pregnancy complications such as preeclampsia (PE), a condition characterized by maternal inflammation, are associated with cognitive deficits in offspring, both in childhood and adulthood.
Animal models support this idea, suggesting that exposure to high levels of maternal inflammation or stress during pregnancy can impair fetal brain development. These factors particularly affect regions critical to memory, such as the hippocampus, resulting in long-term deficits.
However, there is a significant gap in studies examining how these adverse exposures affect men and women differently. This distinction is essential because areas of the brain involved in memory, such as the hippocampus and prefrontal cortex, develop differently in each sex.
In addition, sex hormones and immune cells play important roles during critical periods of fetal development, influencing the formation of these regions. As we age, brain activity in regions associated with memory changes.
Regions such as the hippocampus, prefrontal cortex, and posterior parietal cortex are particularly involved in memory formation and retrieval. In women, menopause and the decline of hormones such as estradiol are linked to significant changes in the functioning of these areas, which can impact memory.
Men, on the other hand, have different patterns of brain connectivity, suggesting alternative mechanisms to compensate for cognitive aging. A recent study investigated the impact of adverse prenatal exposures, such as elevated levels of maternal inflammatory cytokines, on the memory performance of adult offspring, focusing on gender differences.
The researchers followed offspring exposed to high levels of maternal inflammation during a critical period of brain development and assessed them over 50 years. Men exposed to these conditions performed worse on memory tests and had lower activity in areas such as the hippocampus and prefrontal cortex.
In women, the effects were more pronounced after menopause, with sharp declines in memory performance and greater activation of inflammatory processes.
Functional magnetic resonance imaging (fMRI) results showed that high levels of maternal pro-inflammatory cytokines, such as IL-6 and TNF-α, were significantly associated with changes in brain activity and functional connectivity, with impacts persisting over 50 years.
In contrast, the anti-inflammatory cytokine IL-10 showed no significant association with memory circuitry in midlife. The predictive validity of these exposures was confirmed by their association with academic performance in childhood at age 7, which in turn showed a direct relationship with memory performance in midlife.
The findings also indicated that males are more sensitive to adverse exposures during the prenatal period, while females are more vulnerable later in life, possibly due to hormonal changes during menopause.
In addition, adverse prenatal exposures were associated with activation of the NLRP3 inflammasome in midlife, an immune structure linked to the progression of Alzheimer’s disease. The NLRP3 inflammasome contributes to the accumulation of plaques in the brain and the release of inflammatory substances that affect memory.
These findings highlight the importance of identifying early risk factors to develop effective preventive strategies. Given the increase in life expectancy and the increasing prevalence of Alzheimer’s disease, it is crucial to understand how prenatal exposures may influence the risk of cognitive impairment decades later.
The study reinforces that the impacts of inflammation during pregnancy may persist throughout life, affecting men and women differently.
Ultimately, recognizing these differences is essential for developing personalized interventions. Strategies that consider biological sex, immunological history, and reproductive aging may be more effective in promoting cognitive health and protecting memory across the lifespan.
The impact of adverse levels of maternal prenatal immunity on offspring memory and immune function in midlife differs by sex and reproductive stage. This figure illustrates the overall findings of this study. Adverse prenatal maternal immune activation impacts offspring brain development and immune function with consequences that can be seen as early as age 7, i.e. impacting academic performance, and with sex-dependent effects across the lifespan on midlife outcomes that are revealed in postmenopausal women, adjusted for chronological age.
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Prenatal immune origins of brain aging differ by sex
Jill M. Goldstein, Kyoko Konishi, Sarah Aroner, Hang Lee, Anne Remington, Tanuja Chitnis, Stephen L. Buka, Mady Hornig & Stuart A. Tobet
Molecular Psychiatry (2024)
Abstract:
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.
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