Menopause and dementia risk – Does menopause increase women’s risk for dementia? It might be a surprising question but there is increasing evidence that the hormonal changes during menopause can have a significant impact on our cognitive health and future dementia risk.

How can menopause potentially influence our risk for dementia in the future? And can Hormone Replacement Therapy potentially mitigate this risk?

Let’s find out.

Menopause and cognitive changes

Menopause (from Greek ‘menos’ = month; ‘pause’ = to cease; meaning the stopping of the monthly period) is a significant event in a woman’s life, similar to the menarche (the start of menstruation). To many, it might be a relief when menopause arrives but what actually happens physiologically during menopause and how does this affect our brain?

The key hormone which changes during menopause is estrogen. Estrogen is a key hormone in our bodies (not only in women but also in men who have a lower concentration of estrogen circulating their bodies). Not only does estrogen determine many of our bodily features but also has an important role in our sexual functions and women’s menstrual cycle. What is maybe less known is that estrogen has also very important functions in our brain. Estrogen is important for our nerve cells, as it helps them to regenerate if the nerve cells get damaged. There is also evidence that estrogen impacts chemicals that are important for nerve cells to communicate with each other, so-called neurotransmitters. Estrogen is particularly important for one neurotransmitter – Acetylcholine, which is critical for attention and memory cognitive processed in the brain. Overall, estrogen has, therefore, not only important roles for our hormonal physiology but also our brain health and even cognition.

This critical role of estrogen in cognition explains why women often report a ‘brain fog’, such as problems focusing or remembering things, during or after menopause, when the estrogen levels start to fall significantly. It is the changes in estrogen which seem to be responsible for the cognitive changes. This notion has been further confirmed by studies in women who underwent surgical menopause, by undergoing hysterectomies or oophorectomies (removal of the uterus or ovaries). The removal of the uterus or ovaries causes more direct menopause in women and women undergoing surgical menopause also show cognitive changes, likely again due to the dropping levels of estrogen after the operation. The other important fact to understand is that despite the estrogen levels fall quite rapidly the associated cognitive changes can persist for many years after menopause.

What can we do about this? Is there not Hormone Replacement Therapy, which replaces the estrogen lost during menopause. Could this therapy not alleviate the cognitive symptoms?

Hormone Replacement Therapy

The potential benefit of giving women Hormone Replacement Therapy to alleviate cognitive symptoms after menopause has been investigated for the last 10-15 years. But the results of these investigations and their clinical trials were puzzling to the scientists. Some clinical trials found beneficial effects on cognition for the women, while others found not effects and worse some even reported a worsening of cognition after initiating Hormone Replacement Therapy. How is that possible? Should estrogen not improve cognition since it is so important for many cognitive (and brain) processes?

Enter the ‘Critical Window Hypothesis’.

The Critical Window Hypothesis is a theory developed based on these conflicting clinical trials findings. In essence, the results from the clinical trials suggest that the timing of the Hormone Replacement Therapy is critical to help women with their cognition. Specifically, starting to administer Hormone Replacement Therapy right at the beginning of menopause or during menopause (so-called peri-menopause) has been shown to have beneficial effects on cognition for women in those clinical trials. However, administering Hormone Replacement Therapy after menopause has shown to have actually adverse effects on cognition in women. To put it differently, once menopause is over, administering estrogen is too late to boost cognition, even worse it can actually worsen the cognition then. So, the ‘critical window’ for Hormone Replacement Therapy is to start it during menopause.

This causes somewhat a dilemma, for example, should all women be put on Hormone Replacement Therapy? Since some women do not report cognitive changes after menopause, is it justified to give everyone additional estrogen ‘just in case’? It might be not advisable to prescribe every woman Hormone Replacement Therapy, in particular if they actually do not need it. So, we should take the Critical Window Hypothesis by face value, as a hypothesis that needs to be confirmed in future clinical trials investigating directly if the timing of Hormone Replacement Therapy makes a difference to cognitive health later on.

What is the relevance for dementia?

Menopause and dementia risk

Not only does menopause and associated estrogen changes impact women’s cognition but there is also increasing evidence that menopause increases the risk for dementia in women. Several studies over the years suggested that women, in particular in the decade after menopause and under the age of 70 are at an increased risk of developing dementia, compared to men. This notion was supported by a more recent study in a very large cohort of 50,000 women. The data clearly showed that women were indeed at a higher risk of dementia below the age of 70, following the decade after menopause, compared to men. By contrast, the risk for dementia was similar in women and men above the age of 70, indicating that the effects of menopause after 70 are negligible compared to before. This suggests that the risk of dementia for women, compared to men, is higher shortly after the menopause. It also dovetails the ‘critical window hypothesis’, suggesting that there is a time-limited effect of the hormonal changes on the risk for dementia. It is therefore the time right after menopause that is the most vulnerable in terms of dementia risk for women.

What is the physiological mechanism behind this increased risk for dementia due to menopause?

Again, estrogen seems to be a key factor. We know already that estrogen is important for our cognition, nerve cell repair and also the neurotransmitter Acetylcholine. All these factors are also critical in dementia, and particularly Alzheimer’s disease, where we see a change in cognition and increasing nerve cell damage because of the accumulation of proteins. But the most intriguing is the reduction (scientific-speak: depletion) of Acetylcholine, the neurotransmitter. Depletion of Acetylcholine is a critical factor in the beginning stages of Alzheimer’s disease, where the reduction of this neurotransmitter contributes to the attention and memory symptoms in people with this type of dementia. Indeed, the medication prescribed to people with early Alzheimer’s disease, for example, Aricept, are meant to boost Acetylcholine in the brain to help their attention and memory. This further suggested that estrogen not only had a protective effect on cognition but also on the development of dementia. The exact mechanism on how estrogen can be protective of dementia are yet to be elucidated. There is clearly more work to be done to understand exactly how estrogen (and other hormones) influence our overall brain health and incidentally our risk for dementia.

It brings us back to the thorny question as to whether Hormone Replacement Therapy should be given to women to reduce their risk for dementia below the age of 70?

Clearly not an easy question, as we already know from the critical window hypothesis that the timing of administering estrogen via Hormone Replacement Therapy is critical. But even if we time it correctly, should it be suggested that all women should take Hormone Replacement Therapy to reduce their risk for cognitive changes and potentially dementia. Clearly, it is not advisable to prescribe to every woman Hormone Replacement Therapy but how can we better identify women who might be at the highest risk of cognitive impairment or dementia after menopause.

A recent study has shed light on this issue by highlighting that genetic risk might play a critical role in determining such ‘high-risk’ women. The gene of particular interest is Apolipoprotein E (also called APOE), which is the most common genetic risk factor for Alzheimer’s disease. We inherit one gene from each of our parents, which will determine our genotype and hence genetic risk for Alzheimer’s disease. If we inherit two APOE 3 genes from our parents then we are not at increased genetic risk of Alzheimer’s disease. However, if we inherit one APOE 3 and one APOE 4 gene from our parents, we have a 4-fold increased risk of dementia (admittedly this is still quite a low risk in the bigger scheme of things and only ~20% of the population has this genotype). The risk gets more significant serious if we inherit two APOE 4 genes, which increases our risk of Alzheimer’s disease 12-fold, albeit this genotype is only present in ~2% of the population. So, overall the genotype determines our risk for Alzheimer’s disease but the majority of the population (75%) will have two APOE 3 genes and hence are not at increased genetic risk for Alzheimer’s disease.

Coming back to the menopause study. This study investigated whether the genetic risk made a difference to the risk of cognitive impairment and dementia in women. Indeed, that is exactly what they found, that women with the APOE 4 genotype were at a higher risk of cognitive impairment and dementia shortly after menopause. The exact reason why the APOE genotype and menopause are related is not yet clear, however, what is clear is that Hormone Replacement Therapy might be in particular beneficial for women at increased genetic risk (APOE 4) for Alzheimer’s disease. This clearly needs to be investigated in future clinical trials but shows promise that the risk posed by menopause on the risk of cognitive impairment and dementia might be potentially modifiable in ‘high-risk’ women.

Where does this leave us?

Risk factors for dementia seem to emerge from everywhere (see also my recent entry on this here) and it might seem scary that menopause might be another risk factor for dementia. How many risk factors can there be out there? But the key to remember is that we just need to be aware of those risk factor as we can then try to influence them. Even though we cannot change menopause as it is part of women’s physiological ageing process, we can influence its risk for dementia. In particular, we now know that the impact of the menopause on dementia risk is time-limited, affecting mostly women below the age of 70 when dementia is less common in general. The other positive note is that even if certain women are at a higher risk for dementia due to menopause, there are existing treatments, such as Hormone Replacement Therapy, to potentially reduce the risk. Being aware of these factors can therefore inform future dementia risk and treatment approaches.

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Summary

There is clear evidence that menopause has an effect on the cognition of women. The effect is mostly explained by changes to the levels of estrogen circulating in the body and the brain. Estrogen emerges as a hormone that has not only functions for our reproduction but is also critical in maintaining our brain health. Still, Hormone Replacement Therapy should be undertaken with caution as the timing (critical window) of the estrogen replacement has a significant impact on whether its effects are beneficial or adverse on women. This matters as well for the risk of dementia. The reduction in estrogen can also increase in women the risk for dementia, albeit the increased risk, compared to men, is confined to the age under 70. After the age of 70, it is clear that the risk for dementia is similar in men and women while taking into account that women on average live longer. Recent findings suggest that the genetic risk (APOE) might in particular increase the risk for women to develop dementia after menopause, which is currently further investigated. Future dementia risk and treatment approaches will likely take into account the impact menopause has on women’s risk for dementia.

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