Intro: How early brain development influences aging and memory
Population aging in the United States is accelerating, with projections showing a growing share of adults aged 65 and older. While lifestyle, genetics, and health conditions influence memory in later life, mounting evidence points to prenatal periods as a foundational phase that can shape memory circuits for decades. A contemporary line of research led by Jill Goldstein, PhD, MPH, and colleagues at the Innovation Center on Sex Differences in Medicine at Mass General is exploring how fetal exposure to maternal immune activity may set the trajectory for memory function across the lifespan.
Fetal origins of memory impairment: the role of maternal immune activation
The central hypothesis is that adverse maternal immune activation — notably elevated pro-inflammatory cytokines — can redirect the development of memory networks in the fetal brain. The brain regions most tied to memory, including the hippocampus and prefrontal cortex, are among the most sexually dimorphic, suggesting that prenatal exposures may exert sex-specific effects that persist into adulthood.
In this framework, cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) act as critical signals during late pregnancy, a key window for brain sexual differentiation. These signals can influence how neural circuits wire up and how the stress axis, of which the hypothalamic-pituitary-adrenal (HPA) axis is a part, is programmed to respond later in life.
Study design: following a rare prenatal-to-midlife cohort
The Mass General team leveraged a rare longitudinal resource: a cohort of 204 adult offspring tracked from prenatal life into midlife, derived from the New England Family Study (NEFS). The original NEFS enrolled over 17,000 pregnancies between 1959 and 1966, with maternal blood samples collected during pregnancy and stored for future analyses. In midlife (ages 45–55), participants underwent comprehensive neuropsychological testing and advanced brain imaging, including functional and structural MRI while performing episodic memory tasks.
Key memory assessments included the Face-Name Associative Memory Exam (FNAME) for associative memory and the Selective Reminding Test (SRT) for verbal memory, complemented by imaging that captured brain activity and connectivity within memory networks.
Key findings: sex-specific, brain-region–specific effects lasting into midlife
The researchers found that higher prenatal exposure to pro-inflammatory cytokines (notably IL-6 and TNF-α) was linked to enduring changes in memory performance and brain circuitry that differed by sex and by reproductive status in later life.
- Memory performance: Adults whose mothers had higher IL-6 and TNF-α levels during late second to early third trimester performed worse on memory tests in their 40s and 50s. The same prenatal exposure was also associated with poorer academic outcomes at age 7, underscoring lifelong consequences.
- Brain activity and connectivity: fMRI revealed altered activity and connectivity in memory-related regions, especially within the hippocampus and prefrontal cortex, among those exposed to higher prenatal inflammation.
- Sex and menopausal status: Effects were more pronounced in women, particularly postmenopausal women. Pre-menopausal women showed negligible impairment, highlighting reproductive history as a moderator of vulnerability.
- Immune system changes: In post-menopausal women with prenatal exposure, there were lasting alterations in immune signaling, including activation of the NLRP3 inflammasome, a key component in inflammatory pathways linked to neurodegenerative disease processes.
Clinical implications: from pregnancy to aging prevention
These findings support a life-course approach to brain health. If maternal immune milieu can influence lifelong memory trajectories, then monitoring and potentially moderating immune activation during pregnancy could reduce later-life cognitive risk. The research also emphasizes sex- and reproductive history as essential factors in assessing memory aging risk, suggesting that prevention and monitoring strategies in women may need to be tailored according to menopausal status and reproductive history.
Prospective interventions might include strategies to minimize adverse immune signaling during pregnancy, refine risk assessment for memory decline, and develop targeted cognitive and neural monitoring for individuals with elevated prenatal inflammatory exposure. While more work is needed to translate these findings into clinical practice, the study adds a compelling dimension to our understanding of how memory circuits are sculpted long before birth and continue to evolve through adulthood and aging.
Takeaway
The roots of aging-related memory changes can extend back to fetal development, with the prenatal immune environment leaving lasting marks on brain circuitry. Recognizing sex differences and reproductive history as central to memory aging could drive earlier, more personalized strategies to preserve memory across the lifespan.
