Reproductive history may influence dementia, Alzheimer’s risk
Fewer children, older age at menarche, and a higher number of miscarriages are among factors that may raise a woman’s risk of dementia, according to a study presented at the recent Alzheimer’s Association International Conference (AAIC 2018).
Researchers used data from the Kaiser Permanente Northern California system to identify 14,595 women aged 40–55 years between 1964 and 1973 (68 percent Caucasian), of whom 98 percent had ≥1 child. Average age at menarche and menopause was 13 and 47 years, respectively, while average reproductive period was 34 years. Seventy-five percent of the 6,751 women who answered questions on miscarriage had experienced ≥1 miscarriage.
Compared with women with one child, women with ≥3 children had a 12 percent lower risk of dementia (hazard ratio [HR], 0.88, 95 percent confidence interval [CI], 0.81–0.95), with results mostly unchanged after taking into consideration mid- and late-life health conditions. [AAIC 2018, abstract P3-587]
Menarche at age ≥16 years was associated with a higher risk of dementia compared with menarche at age 13 years (HR, 1.31, 95 percent CI, 1.05–1.62). Early menarche (age ≤9 years) was also associated with an elevated risk of dementia (HR, 1.40, 95 percent CI, 0.83–2.37), though the finding was not significant.
Early menopause (age ≤45 years) was also associated with an increased risk of dementia compared with women who experienced menopause after age 45 years (HR, 1.28, 95 percent CI, 1.14–1.44). Similarly, shorter reproductive periods (years between menarche and menopause) was also tied to a higher risk of dementia, with a 33 percent increased risk among women with reproductive periods of 21–30 years compared with 39–44 years (HR, 1.33, 95 percent CI, 1.11–1.58) and each additional year of reproductive period tied to a 2 percent decreased risk of dementia.
Women who did not experience a miscarriage had a 20 percent lower risk of dementia compared with women with ≥1 miscarriage, with each additional miscarriage associated with a 9 percent elevated risk of dementia.
“Women have substantially higher prevalence of dementia compared [with] men but female sex-specific risk factors over the life course are not well understood,” said study author Dr Paola Gilsanz from Kaiser Permanente Northern California Division of Research, Oakland, California, US. “[W]e aimed to identify female-specific risks and protective factors impacting brain health, which is critical to diminishing the disproportionate burden of dementia experienced by women,” she said.
“Reproductive events that signal different exposures to oestrogen … may play a role in modulating dementia risk. This contributes to a growing body of evidence that exposure to different forms of oestrogen across the life course impact brain health,” said Gilsanz.
Immune system may influence pregnancy-Alzheimer’s link
The link between pregnancy and a lower risk of Alzheimer’s disease (AD) was demonstrated in a case-control, cross-sectional study from the UK conducted among 133 women aged 70–100 years. In this study, for every additional month spent pregnant, the risk of AD reduced by 5.5 percent (p=0.02). [AAIC 2018, abstract 25107]
A higher number of first trimesters was associated with a reduced risk of AD (p<0.01), though the link was not apparent with a higher number of third trimesters (p=0.31).
“We are intrigued by the possibility that pregnancy may reorganize the mother’s body in ways that could protect her against developing Alzheimer’s later in life,” said study author Assistant Professor Molly Fox from the University of California, Los Angeles in California, US.
According to the researchers, two possible mechanisms could explain the pregnancy-Alzheimer’s link – the oestrogen hypothesis and the immunoregulation hypothesis.
“We hypothesize[d] that women who spen[t] more cumulative months pregnant may experience reduced risk of AD later in life via improved regulation of inflammation,” said the study authors. “Women with higher gravidity may experience increased regulatory T-cell frequencies in the long-term. Such an increase in immunosuppressive function might protect against AD pathogenesis, because depleted immunoregulatory mechanisms have been implicated in AD aetiology.”
“Our observation that more first-trimesters [but not third-trimesters] conferred protection against AD is more consistent with pregnancy’s persisting immunological effects, which are driven by early gestational physiology, than the oestrogenic exposures associated with pregnancy, which are greatest in late gestation,” they said.
“Improvement in the body’s ability to suppress inflammation could be important in understanding how pregnancy may influence Alzheimer’s risk. Oestrogen is still probably neuroprotective, just might not explain how pregnancy affects Alzheimer’s risk,” said Fox.
“More research is needed in this area, because having a better understanding of sex-specific risk factors across the lifespan may help us discover – and eventually apply – specific prevention strategies for different populations of people with Alzheimer’s and other dementias,” said Dr Maria Carrillo, Chief Science Officer for the Alzheimer’s Association.