Memory in old age may depend our mothers' immune state

About three quarters of people aged 65 and older report problems with their memory, and according to the NHS, in the UK 1 in 11 people aged over 65 have dementia. A better understanding of the causes of brain aging and when it begins, however, could help to reduce these numbers. Recent work in Molecular Psychiatry provides one such useful insight, with researchers finding that a mother's immune state while she is pregnant can have a lasting effect on her child's brain health.

Jill M. Goldstein at Harvard Medical School and colleagues analysed data on 204 men and women who are taking part in a long-term study in the US. While they were foetuses, about half were exposed to higher-than-normal levels of immune markers, such as the cytokines IL-6 and TNF-alpha. This was as a result of their mother suffering from an illness or medical condition, such as pre-eclampsia.

When the participants were between the ages of 45 and 50, they completed a battery of memory tests. In one test, for example, they had to learn to pair people's faces with specific jobs. In another, memory-related regions of their brain were scanned using fMRI while they completed tasks that required them to remember words or sentences. 
Goldstein and her colleagues found links between results on these memory tests and heightened maternal immune activity while they were in the uterus – those links, however, were different for men and women.

For men, exposure to higher levels of IL-6 and TNF-alpha while in the uterus was linked to significantly poorer memory performance overall, as well as reduced activity in the prefrontal cortex and the hippocampus while committing words to memory.

For the women, exposure to higher levels of these immune markers was linked to significantly poorer memory performance and disruptions to memory circuits in the brain only for those who were post-menopausal. This finding suggests that when female reproductive hormones drop off after menopause, these deteriorations become apparent. (Interestingly, recent research has also highlighted that menopausal hormone therapy is associated with higher levels of amyloid plaque buildup in women with APOE ε4.)

Overall, the results support the idea that, while we're still in the womb, our mother's immune state can have a lasting impact on our own brains, the team writes. This "may set the stage for how the brain ages across the lifespan and contribute to risk for memory decline and resilience," they add.

Other work supports the idea that experiences in the uterus can affect memory into the future. For example, work on mice has linked heightened maternal immune activation while in the uterus to abnormalities in memory regions of the brain, and, when the mice reach old age, to some brain changes that resemble those seen in people with Alzheimer's disease.

The team now plans to continue to study the participants, to look for any links between prenatal immune activity and signs of Alzheimer's disease in later life. They also want to explore exactly how the immune state of a pregnant person affects the development of their baby's brain — and whether harmful brain changes can be prevented.

Understanding early developmental risks could make it possible to identify people who are most at-risk of poorer brain health in older age. This is particularly important in the wake of the Covid-19 pandemic, they write, because worldwide, countless women have been infected with the virus while pregnant. If researchers can better understand the impact of heightened immune activity in a pregnant woman on their child's brain, it might be possible to develop strategies for early interventions.

Read the paper in full:

Goldstein, J.M., Konishi, K., Aroner, S. et al. (2024). Prenatal immune origins of brain aging differ by sex. Molecular Psychiatry. https://doi.org/10.1038/s41380-024-02798-w

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