Estrogen exposure in reproductive history and risk of Alzheimer’s disease in midlife women

A new study found that reproductive history indicators were not directly linked to cognitive measures of Alzheimer’s disease (AD) in midlife women.

The study examined connections between indicators of estrogen exposure from women's reproductive history and brain magnetic resonance imaging (MRI) biomarkers of AD in midlife.

However, the study in Neurology, the medical journal of the American Academy of Neurology, concluded that voxel-wise gray matter volume (GMV) in temporal regions was positively associated with memory and global cognition scores.1

The observational cohort study recruited 99 cognitively normal women and 29 cognitively normal men between the ages of 40 and 65 years with risk factors for late-onset AD, such as, a family history and/or the Apolipoprotein E epsilon 4 (APOE-4) genotype.

The study was conducted at Weill Cornell Medicine in New York, New York between 2018 and 2021. All participants received clinical, cognitive, laboratory, and brain MRI exams within roughly 3 months of recruitment.

The cohort included 15 premenopausal, 35 perimenopausal, and 49 postmenopausal women, 13 of whom reported a previous hysterectomy and/or oophorectomy.

Among 98 women, 9% were currently hormonal contraceptives (HC) users, 53% past users, and 38% never users. For those who provided information on duration of HC use, the average was 13 years.

Among 96 women, 21% had no children, 17% had 1 child, and 62% had 2 or more children.

Among the 29 men, 21% had no children, 7% had 1 child, and 72% had at least 2 children.

Negative connections between menopause status and GMV were observed in inferior temporal gyrus (P = 0.049), and borderline negative associations in inferior frontal gyrus (P = 0.059), in the right hemisphere.

All menopausal groups had lower GMV in AD-vulnerable regions versus men, with perimenopausal and postmenopausal groups also exhibiting lower GMV in temporal cortex as compared to the premenopausal group.

Reproductive span, number of children and pregnancies, use of hormone therapy (HT), and HC were positively linked to GMV, primarily in the temporal cortex, frontal cortex, and precuneus, independent of age, APOE-4 status, and midlife health indicators.

For every year increase in reproductive span, GMV increased by 0.01 units. Adjusted by age and total intracranial volume, a reproductive span of at least 39 years was linked to a larger GMV of 0.05 units compared to a reproductive span of less than 39 years (P = 0.013).

Likewise, in women, the number of children was positively connected to GMV in inferior and middle frontal gyri, and middle and inferior temporal gyri (P≤0.21). For example, GMV increased by 0.02 units in these regions for every additional child (P≤ 0.001).

Among men, there were no significant associations between number of children and GMV.

On the other hand, there were positive connections between HT use and GMV in superior frontal gyrus and supramarginal gyrus, bilaterally; middle temporal gyrus and frontal pole of the right hemisphere; and inferior temporal gyrus, fusiform gyrus, and medial frontal gyrus of the left hemisphere.

“We caution that present results were found in healthy, well-educated, carefully screened research participants, including mostly Whites of generally middle/high socioeconomic status, which limits the generalizability of our findings,” wrote the authors.

They also noted that more studies are needed to clarify sex-specific biological pathways through which reproductive history impacts cognitive aging and AD-risk.



1. Schelbaum, E, Loughlin L, Jett S, et al. Association of reproductive history with brain MRI biomarkers of dementia risk in midlife. Neurology. Published online November 3, 2021. doi:10.1212/WNL.0000000000012941