Post Reprod Health. 2019 Nov 5:2053369119883485. doi: 10.1177/2053369119883485. [Epub ahead of print]
There is increasing evidence that menopausal changes can have an impact on women’s cognition and potentially, the future development of dementia. In particular, the role of reduced levels of estrogen in postmenopausal changes has been linked to an increased risk of developing dementia in observational studies. Not surprisingly, this has led to several clinical trials investigating whether postmenopausal hormone replacement therapy can potentially delay/avoid cognitive changes and subsequently, the onset of dementia. However, the evidence of these trials has been mixed, with some showing positive effects while others show no or even negative effects. In the current review, we investigate this controversy further by reviewing the existing studies and trials in cognition and dementia. Based on the current evidence, we conclude that previous approaches may have used a mixture of women with different genetic risk factors for dementia which might explain these contradicting findings. Therefore, it is recommended that future interventional studies take a more personalised approach towards hormone replacement therapy use in postmenopausal women, by taking into account the women’s genetic status for dementia risk.
Summary and Outlook
Taken together, there is increasing evidence for not only a correlational, but also a causal link between menopausal hormone changes and cognition as well as dementia, which has so far been under-explored in the literature. Despite the exciting findings discussed, it emerges that there is complex interaction between menopausal stages, HRT and genetic status (in particular for the APOE genotype) which appears to underlie cognitive deficits and potentially the onset of incipient dementia. In particular, the specific biological mechanisms which link estrogen to cognitive changes and incipient dementia require further investigation. In this regard, the impact of genetic risk factors, such as APOE or estrogen receptors encoded by ESR1/2 genes, seems to be critical to our understanding of the risk profile of women for developing dementia across menopausal stages. Delineating those contributions might help identify women who are at a higher risk for dementia post-menopause, based on their genotype status. This would enable the designing of much more targeted longitudinal and interventional studies for such women, who are potentially at the highest risk of cognitive decline and dementia. In turn, this might also reduce the admixture of women in clinical trials to increase the statistical power for interventions and reduce the outcome variability. Furthermore, on the cognitive testing side, it is recommended that a more systematic approach be adopted for testing cognitive performance in menopausal women objectively. In particular, more detailed and specific tests to detect potentially incipient dementia processes would be beneficial, as currently most studies and trials use crude cognitive screening tests. Of relevance in this regard might be novel, more dementia pathology-specific tests in spatial navigation, which have been shown to be related to entorhinal cortex integrity and underlying amyloid/ tau pathology. This would allow the delineation of more general cognitive effects of menopausal hormonal changes from dementia-specific ones, again informing future clinical trials. Finally, the identification of such specific menopausal phenotypic and genotypic changes would allow a more personalised approach to identify women ‘at-high-risk’ of developing dementia, which in turn would allow earlier treatment with a potential to alleviate or even delay the onset of the disease