According to data collected in 2024, there are approximately 60 million adults aged 65 and older living in the United States, representing about 18% of the total population. This number is projected to increase significantly over the coming decades. By 2050, the number of people in the United States aged 65 and older is projected to reach approximately 82–84 million; up to 75% of these adults will report memory-related problems and about 13.8 million people are expected to have Alzheimer’s disease (AD).
About two-thirds of this aging population are women. Given that women and men age differently and exhibit distinct patterns of susceptibility to Alzheimer’s disease—with women facing a higher lifetime risk of AD and greater disease burden compared to men—it is essential to understand sex-specific factors contributing to memory decline and resilience. Jill Goldstein, PhD, MPH, and her team of researchers from the Innovation Center on Sex Differences in Medicine at Mass General have focused on identifying sex differences in the process of brain development and aging. Systematically studying the effects of sex on aging is fundamental given that the regions central to memory—including the hippocampus and prefrontal cortex—are among the most sexually dimorphic areas of the brain.
Fetal Origins of Memory Impairment
While many factors across the lifespan affect risk for and resilience to memory decline, there is growing evidence to indicate that the roots of brain aging begin much earlier, during fetal development. In utero, the fetal brain undergoes rapid growth and differentiation, and it is during this phase of development that the brain is particularly vulnerable to intrauterine and environmental exposures. While early research focused on environmental factors, including toxins and chemicals, on the developing brain, more recent research has highlighted the detrimental effects of adverse maternal immune activation. Adverse alterations in the immune environment of the mother may alter fetal brain development, and there is a growing body of evidence to indicate that these effects can persist for decades.
Dr. Goldstein and her research team hypothesize that fetal exposure to adverse maternal immune activation—specifically elevated levels of pro-inflammatory cytokines—can alter the development of brain circuits that are essential to memory. Furthermore, the effects of maternal immune activation are believed to differ between males and females, and it is likely that these changes in brain function persist well into adulthood. Dr. Goldstein notes, “Brain aging is also about brain development, and understanding sex differences in brain development is critical to understanding sex differences in the aging brain.”
Study Design
To test this hypothesis, the researchers drew upon a rare, longitudinal cohort of 204 adult offspring, followed from the prenatal period into midlife (approximately to age 50). Participants were part of the New England Family Study (NEFS), which originally enrolled over 17,000 pregnancies between 1959 and 1966. During the study, maternal blood samples were collected in mid- to late-pregnancy and were stored for future analyses.
Adult offspring between the ages of 45 and 55 years were recruited from the original NEFS cohort based on the availability of stored maternal serum samples and complete developmental records from birth through childhood.
The research team measured concentrations of pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor (TNF-α) in the archived maternal serum collected during the late second to early third trimester—a key period of brain sexual differentiation. These cytokines are known to be important co-activators of the hypothalamic-pituitary-adrenal (HPA) axis and act on receptors densely located in brain regions essential to memory, including the hippocampus and paraventricular nucleus of the hypothalamus.
In midlife, the adult offspring underwent detailed clinical, neuropsychological, and brain imaging assessments. Functional and structural MRI were conducted while participants performed episodic memory tasks. Associative memory was measured using the Face-Name Associative Memory Exam (FNAME), and verbal memory was evaluated using the Selective Reminding Test (SRT).
Key Findings
The researchers found that adverse maternal immune activation (indicated by elevated levels of pro-inflammatory cytokines) during a critical period of brain development led to long-lasting effects on immune function and memory circuitry persisting from childhood to midlife. The effects of this exposure were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent. In contrast, the anti-inflammatory cytokine IL-10 showed no significant associations.
Effects on Memory Performance: The study showed that in utero exposure to pro-inflammatory cytokines (higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in memory performance. Adults exposed to higher prenatal immune activation performed worse on memory tasks at ages 45-55 years. Exposure to maternal immune activation in utero was also associated with worse academic performance at 7 years of age.
Effects on Brain Activity and Connectivity:The study showed that in utero exposure to pro-inflammatory cytokines was significantly associated with sex differences in the activity and connectivity of brain regions underlying memory circuitry and function. Changes noted on fMRI included alterations in connectivity within the hippocampus and prefrontal cortex.
Effects in Pre- vs. Post-Menopausal Women: The study demonstrated that adverse effects of prenatal immune activation (i.e., higher maternal IL-6 and TNF-α) on memory circuitry and function (including altered brain activity and connectivity) were most evident in postmenopausal women. Similarly, declines in memory performance on neuropsychological tests were also primarily noted in postmenopausal women, with negligible effects observed in premenopausal women. These findings highlight reproductive status as a modulator of vulnerability.
Effects on Immune Function: In addition to its effects on memory and brain circuitry, the study found lasting changes in immune function among adults exposed in utero to higher maternal IL-6 and TNF-α levels. In post-menopausal women, exposure to elevated prenatal levels of pro-inflammatory cytokines was associated with activation of the NLRP3 inflammasome (an immune complex that triggers inflammation in response to cell stress), which plays a central role in inflammatory signaling and has been implicated in the pathogenesis of Alzheimer’s disease.
Clinical Implications
The findings of the current study underscore the need for a life-course approach to brain health, recognizing that the roots of aging-related cognitive decline begin before birth. Being able to identify dysregulation of the maternal immune milieu as a modifiable risk factor could open up avenues for developing early interventions — for example, immune monitoring during pregnancy — in order to reduce long-term risk of memory impairment and Alzheimer’s disease. Clinically, greater awareness of how sex and reproductive history shape cognitive aging could guide tailored monitoring and prevention strategies, particularly among women at elevated risk.
As our population ages and the burden of Alzheimer’s disease grows, early interventions focusing on minimizing the negative effects of brain aging—potentially even in the prenatal period— are critical for shifting the trajectory of cognitive decline. Future research should aim to clarify which maternal immune exposures and level of exposure pose the greatest risks, investigate protective factors that confer resilience, and determine whether modification of maternal health during pregnancy can improve memory outcomes decades later. Ultimately, translating these discoveries into screening, counseling, and risk-reduction interventions could transform how clinicians support cognitive health across generations.
Read More
Goldstein JM, Konishi K, Aroner S, Lee H, Remington A, Chitnis T, Buka SL, Hornig M, Tobet SA. Prenatal immune origins of brain aging differ by sex. Mol Psychiatry. 2025 May; 30(5):1887-1896.
Jill M. Goldstein, PhD, MPH is a clinical neuroscientist and Professor of Psychiatry and Medicine at Harvard Medical School. She is the Founder and Executive Director of the Innovation Center on Sex Differences in Medicine at Massachusetts General Hospital, where she also holds the Helen T. Moerschner Endowed Research Institute Chair in Women’s Health. Over the past three decades, Dr. Goldstein has led pioneering research on sex differences in brain development, aging, and disorders such as depression, cardiovascular disease, and Alzheimer’s disease. Her interdisciplinary work integrates brain imaging, genetics, neuroendocrinology, and immunology to uncover how prenatal and early-life exposures shape lifelong cognitive and physiological outcomes.
