Loss of ovarian hormones is detrimental in early disease stages of mouse models of Alzheimer’s disease and multi-etiology dementia

TL;DR

This study shows that losing ovarian hormones during surgical menopause worsens early Alzheimer's and dementia symptoms in female mice, highlighting the protective role of these hormones.

Contribution

The novel finding is that ovarian hormone loss exacerbates early-stage Alzheimer’s and multi-etiology dementia pathology in female mouse models.

Findings

Loss of ovarian hormones impairs spatial learning and memory in female mice.

Ovarian hormone loss increases insoluble Aβ levels and astrogliosis in the hippocampus.

Microglial response is impaired across multiple brain regions following hormone loss.

Abstract

Up to 80% of Alzheimer’s disease (AD) patients suffer from brain vascular damage resulting in multi-etiology dementia (MED). Sex is a well-known risk factor for dementia; out of three AD patients two are women. 17β-estradiol, a predominant ovarian hormone in woman before menopause, is known to have beneficial effects on the cerebrovasculature, neuroinflammation and neuroprotection. Here, we investigated the consequences of the loss of ovarian hormones caused by surgical menopause (ovariectomy) on AD and MED.

The AppNL−F knock-in mice were used to model AD. At about 5.5 months of age, a stage corresponding to early disease pathology, female AppNL−F mice were subjected to ovariectomy (OVX) or sham surgery (Intact) and left to recover for 3 weeks to clear any endogenous gonadal hormones. In half of the mice from each group, MED was modeled using chronic cerebral hypoperfusion (unilateral carotid artery occlusion), a model of vascular contributions to cognitive impairment and dementia (VCID). Control animals (AD only model) received sham surgery. Mice were then subjected to a battery of behavioral tests before being euthanized and brains were collected to assess pathology.

We found that loss of ovarian hormones impairs spatial learning and memory, impairs activities of daily living, and affects underlying pathology including compromising microglial response. Some of these effects were exacerbated by cerebral hypoperfusion (VCID).

These results shed light on the effects of ovarian hormone loss after surgical menopause in female mouse model of AD and MED in order to better understand sex-specific risk factors.

The online version contains supplementary material available at 10.1186/s13293-025-00795-4.

Alzheimer’s disease (AD) is the most common form of dementia. AD affects more women than men. Most AD patients do not have pure AD, instead they have a mix of AD and other forms of dementia. This mix of multiple dementia types is known as multi-etiology dementia (MED). Vascular dementia, caused by damage to blood vessels, is the most common type of dementia that occurs with AD in MED. Since 2/3 of those with AD are women, we wanted to determine how menopause impacts AD and MED. 17β-estradiol is a prominent hormone produced in the ovaries of women before menopause, but it is lost following menopause. 17β-estradiol is known to have multiple beneficial effects on the brain and the vasculature. Here, we used a genetic mouse model of AD combined with a surgery to reduce blood flow to the brain to model MED. To model loss of ovarian hormones during menopause, we removed the ovaries. We found that menopause caused impairments in some types of learning, memory, and the ability to perform some normal daily activities. Menopause also causes changes in the brain that resulted in worse dementia pathology. Some changes were even more severe in the MED mice compared to AD mice. These results indicate that hormones produced by the ovaries that are lost during menopause are important and protective in models of AD and MED. These findings are important as they will help in future studies for diagnosing and guiding treatment of dementia in female patients.

The online version contains supplementary material available at 10.1186/s13293-025-00795-4.

In mouse models of AD and MED, at a stage that corresponds to early disease pathology, loss of ovarian hormones leads to:

Impaired spatial learning and memory

Impaired activities of daily living

Increased insoluble Aβ levels and astrogliosis in the hippocampus

Impaired microglia response across several brain regions

The online version contains supplementary material available at 10.1186/s13293-025-00795-4.

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