Overview: How early-life factors shape memory in later life
New evidence suggests that critical processes during fetal brain development can influence memory and cognitive resilience decades later. Researchers led by Jill Goldstein, PhD, MPH, from the Innovation Center on Sex Differences in Medicine at Mass General are examining how sex and reproductive history modulate the long-term impact of prenatal exposures on memory circuits. The work highlights a shift in how we think about aging: brain aging is also a story of early brain development and sex-specific trajectories.
Why prenatal immune activation matters
During pregnancy, maternal immune status can affect the fetal environment. Adverse maternal immune activation (MIA) — driven by higher levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) — may alter the development of brain circuits essential for memory. IL-6 and TNF-α are involved in signaling pathways that shape the hypothalamic-pituitary-adrenal axis and impact brain regions like the hippocampus and prefrontal cortex. In contrast, the anti-inflammatory cytokine IL-10 did not show the same associations in this line of research.
The study design: following a rare cohort from birth to midlife
To test the hypothesis, researchers used a rare longitudinal cohort: 204 adult offspring from the New England Family Study (NEFS), originally part of a larger group of over 17,000 pregnancies from 1959–1966. Maternal blood samples were archived from late pregnancy, a key period for brain sexual differentiation. In midlife (ages 45–55), offspring underwent detailed clinical and neuropsychological testing, along with functional and structural MRI while performing episodic memory tasks. Memory was assessed with the Face-Name Associative Memory Exam (FNAME) for associative memory and the Selective Reminding Test (SRT) for verbal memory.
Key findings: sex differences and memory circuits
The study found that prenatal exposure to elevated pro-inflammatory cytokines predicted lasting changes in memory performance and brain activity, with effects that depended on sex, brain region, and reproductive status. Specifically, higher maternal IL-6 and TNF-α levels during late pregnancy were associated with poorer memory performance in adults aged 45–55, and with altered activity and connectivity in memory-related networks, including the hippocampus and prefrontal cortex.
In women, the effects were particularly nuanced and tied to reproductive status. Postmenopausal women showed more pronounced memory declines and altered brain connectivity after prenatal exposure to increased pro-inflammatory signals, whereas premenopausal women exhibited negligible changes. This suggests that reproductive history modulates vulnerability to memory impairment and points to hormonal milieu as a factor in brain aging.
Immune function and aging: a lifelong thread
Beyond memory performance, the research noted lasting changes in immune function among those exposed in utero to higher maternal IL-6 and TNF-α. In postmenopausal women, prenatal exposure linked to activation of the NLRP3 inflammasome — a driver of inflammatory signaling connected to neurodegenerative disease processes, including Alzheimer’s disease. These findings reinforce that aging-related cognitive decline may originate far earlier than previously recognized.
Clinical implications: a life-course view of brain health
The work emphasizes a life-course approach to brain health, recognizing that the seeds of aging-related cognitive decline lie in fetal development. Identifying dysregulation of the maternal immune milieu as a modifiable risk factor could inform pregnancy monitoring and early interventions aimed at reducing long-term memory impairment and Alzheimer’s disease risk. Clinically, recognizing sex and reproductive history as modulators of cognitive aging could guide personalized monitoring and prevention strategies, especially for women at elevated risk.
Future directions
As scientists refine our understanding of how prenatal immune signals shape memory circuits, potential interventions may focus on minimizing maternal inflammation during pregnancy or developing targeted strategies to bolster resilience in offspring, especially across sexes. Ongoing research will help translate these findings into actionable guidelines for maternal health and age-related cognitive prevention.
