KEY TAKEAWAYS
Stress-related immune activity during the late second to early third trimester of pregnancy can have long-term sex-dependent effects on offspring memory circuitry, function, and decline that potentially increase vulnerability for memory disorders, such as Alzheimer’s disease, after menopause. Sex differences in immune function begin in fetal development and, when dysregulated, may have important implications for understanding differences in brain aging. Understanding how these risks originate may lead to new treatments that could be used proactively to reduce disability and develop resilience as the brain ages. 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 new 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.
“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, PhD, MPH, founder and executive director of the Innovation Center on Sex Differences in Medicine of Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, 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 includes 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.”
Authorship: In addition to Goldstein, Mass General Brigham authors include Kyoko Konishi, Sarah Aroner, Hang Lee, Anne Remington, Tanuja Chitnis, and Stuart A. Tobet (also at Colorado State University). Additional authors include Stephen L. Buka at Brown University (longtime collaborator of the NEFS) and Mady Hornig at Columbia University Vagelos College of Physicians and Surgeons.
Disclosures: Goldstein is on the scientific advisory board and has equity interest in Cala Health (a neuromodulation company) but with no conflict of interest related to this study.
Funding: This work was supported by National Institute on Aging (AG0607019 [JMG, PI], K01AG081500 [KK’s time]), National Institute of Mental Health (MH090291), Office of Research on Women’s Health-National Institute of Mental Health (U54 MH118919 [JMG & SAT, mPIs]), and Office of Research on Women’s Health-National Institute of Child Health and Human Development (BIRCWH K12HD051959 [JMG,KR mPIs; in part supporting KK’s time]).
Paper cited: Goldstein JM et al. “Prenatal immune origins of brain aging differ by sex” Molecular Psychiatry DOI: 10.1038/s41380-024-02798-w
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