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A woman's pregnancy history may be linked to her future risk of developing Alzheimer's disease, an analysis of two large longitudinal cohorts suggests.

Women who had an incomplete pregnancy through miscarriage or abortion were less likely to develop Alzheimer's disease in late life, while women who gave birth to five or more children were more likely, reported Ki Woong Kim, MD, PhD, of Seoul National University in South Korea, in .

"Estrogen levels double by the eighth week of pregnancy before climbing to up to 40 times the normal peak level," Kim said in a statement. "If these results are confirmed in other populations, it is possible that these findings could lead to the development of hormone-based preventive strategies for Alzheimer's disease based on the hormonal changes in the first trimester of pregnancy."

"These results highlight the complexity behind sex-specific risk factors and Alzheimer's disease, especially with respect to hormone fluctuations throughout the lifespan," noted Elizabeth Mormino, PhD, of Stanford University in California, who was not involved in the study.

"The dissociable findings related to complete versus incomplete pregnancy is interesting and implies that there is something about the amount of hormonal exposure that is critical for Alzheimer's disease risk among women," Mormino told 乌鸦传媒.

The pregnancy history analysis pooled data from two population-based cohort studies: the Korean Longitudinal Study on Cognitive Aging and Dementia () and the Hellenic Longitudinal Investigation of Aging and Diet () in Greece. Both cohorts evaluated comorbid medical illnesses.

In total, the researchers studied 3,549 women with an average age of about 71, excluding women who took hormone-replacement therapy (HRT) at the time of assessment, or had a history of oophorectomy or hysterectomy. In the combined dataset, 896 women had been diagnosed with mild cognitive impairment and 118, with Alzheimer's disease.

Women who experienced incomplete pregnancies showed half the level of Alzheimer's risk than women who never experienced an incomplete pregnancy (OR 0.43, 95% CI 0.24 to 0.76 for one incomplete pregnancy).

Women who experienced five or more completed pregnancies demonstrated a nearly 1.7-fold higher risk of Alzheimer's than those who had one to four completed pregnancies (OR 1.68, 95% CI 1.04 to 2.72). Grand multiparous women also reported a higher risk of chronic medical illnesses like hypertension, coronary heart disease, and diabetes, but associations with Alzheimer's risk were statistically significant after controlling for these variables.

Among women without dementia, those who experienced one or more incomplete pregnancies had better Mini-Mental State Examination (MMSE) scores than those who never experienced an incomplete pregnancy (P=0.008); those who had five or more completed pregnancies had worse MMSE scores than those with one to four completed pregnancies (P<0.001).

"While this study draws our attention to the risks of a large number of pregnancies on dementia later in life, it falls short on understanding the underlying mechanisms," observed Kejal Kantarci, MD, MS, of the Mayo Clinic in Rochester, Minn., who was not involved in the research.

"This substantial change in hormone levels in a relatively short period may be contributing to the risk of dementia in women with a large number of pregnancies," Kantarci told 乌鸦传媒. "However, we cannot ignore the fact that pregnancy is associated with significant changes in a woman's physiology, in particular cardiovascular physiology, which may lead to noticed or unnoticed complications of pregnancy. And this is not addressed in this study."

Hypertensive pregnancy disorders occur in up to 8% of pregnancies, Kantarci noted, and observational studies show women who have hypertensive pregnancy disorders are at a higher risk of cognitive impairment and later in life."We need to know more about the multiparous women in the study who developed cognitive impairment and dementia later in life, whether they had normal or complicated pregnancies," she added.

The authors noted several other limitations to their research. The number of incomplete pregnancies may have been underestimated: abortions may not have been reported and early miscarriages may not have been recognized. The researchers did not evaluate the timing and cause of incomplete pregnancies or measure postmenopausal serum estrogen levels at the time of diagnosis. And they did not adjust for the influence of the APOE (Apolipoprotein) genotype, because it was assessed in only some participants.

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