Women's brain health: disentangling the role of menopause and ageing

Abstract

Maintaining a healthy brain has been recognised as an important health challenge facing women, given global estimates indicate almost twice as many women die of dementia than men. In part, this is due to their increased longevity, however, this does not explain all of the difference. Other contributors include different exposure to risk factors as well as sex-related physiological differences. This thesis focused on the latter, specifically in relation to possible impacts of menopause, as this stage of life has been suggested to involve particular risks to brain health. To address this question, five studies were conducted to precisely characterise and quantify (1) changes in fat mass during menopause; (2) lipid profile differences during menopause; (3) heterogeneity of menopause nomenclature used in peer-reviewed literature; (4) changes in fat mass and the brain; and (5) menstruation history (including menopausal status and age at menopause) and the brain. Moreover, an important conceptual and theoretical question embedded throughout this thesis has been to determine how much of the observed effects were attributable to ageing, rather than a possible effect of menopause. This has been a significant challenge, given menopause and ageing co-occur.

The first two studies revealed that fat mass was higher in postmenopausal compared to premenopausal women across most measures, with the exception of leg fat which decreased, indicative of a potential change in fat mass distribution after menopause. However, the change in fat mass quantity was predominantly attributable to increasing age with menopause having no detectable additional influence. Furthermore, lipoproteins were significantly higher in postmenopausal women than premenopausal women, with the exception of high-density lipoprotein, which was not significantly different between groups. Measures of ageing explained some, but not all of the differences in lipid levels.

The third study found a significant amount of heterogeneity associated with the definition of "premenopause", compared with "postmenopause".

The fourth study demonstrated that those who suffered from overweight or obesity had smaller hippocampal volumes than those who maintained a normal weight. Furthermore, those who suffered from overweight or obesity in the past, but currently had a normal level of fat mass also had a smaller hippocampus than those who had always maintained a normal weight.

The fifth study revealed an association between menopause and the brain, beyond typical ageing effects. Notably, postmenopausal women had larger brain volumes than premenopausal women but also experience greater decreases in total brain volume, but not hippocampal volume, over time. In addition, delayed age of menopause was negatively associated with brain volume.

The findings from this thesis have demonstrated an association between menopause and the brain, which cannot be uniquely explained by ageing. Specifically, although menopause alone was not found to be negatively associated brain health, it was associated with somewhat poorer brain health when considered concurrently with other changes around menopause. Moreover, when considering that women tend to gain abdominal fat around menopause, as well as develop an unfavourable lipid profile, and given extensive evidence in the literature that higher abdominal fat and lipid levels are associated with a greater risk of cerebro-vascular disease and dementia, hypothesising a link between menopause and poorer brain health seems warranted but will require further confirmation in future research.

As a whole, the findings from this thesis paint an optimistic picture for women's health, since the risk factors identified and linked with deleterious brain health outcomes are modifiable. If adequate support is available at a health policy, clinical and community level, these specific risks to brain health may be reduced or prevented.