Alzheimer’s Disease in Women: Is Menopause the Missing Link?

Nearly two-thirds of those with Alzheimer’s Disease (AD) are women. This has long been attributed to women’s longer lifespans, but it doesn’t tell the whole story. So, why are women more vulnerable? Increasing evidence points to biological differences as an important factor, with growing interest in the hormonal shift during menopause. 

Could this major life transition be the missing link in understanding women’s heightened risk for AD?  

What we know: sex differences in Alzheimer's risk/progression

AD develops gradually on a continuum, with pathological changes in the brain potentially starting decades before diagnosis. This includes the accumulation of hallmark proteins, amyloid-ß and tau, and eventual cognitive decline and neurodegeneration. 

Women not only face a higher risk of developing AD, but they also experience it differently -tending to be diagnosed later, decline faster following diagnosis, and showing a distinct pattern of pathological development, including faster tau accumulation and brain changes. Furthermore, women typically outperform men on cognitive tests throughout life, meaning they may be more resilient to brain changes (termed ‘cognitive reserve’). This may delay diagnosis, particularly as clinical criteria aren’t sex-adjusted, and may mean a steeper decline once this ‘reserve’ is depleted. 

Crucially, the AD continuum highlights that changes may start in mid-life, making this a key period to investigate. For women, not only does mid-life bring multiple demands such as work and caregiving, but also a major hormonal event: menopause. Menopause is a huge endocrinological transition, particularly associated with a decline in oestrogen. So, what does oestrogen do in women’s brains, and what impact might menopause have?

Oestrogen's role in the brain

Oestrogen (particularly 17β-estradiol) is more than a reproductive hormone; it plays a vital role in brain health, supporting many processes, including: 

• Neuronal communication and neuronal plasticity. Oestrogen promotes synaptogenesis (new neural connections), enhances synaptic function (neuronal communication), and supports neurogenesis (creation of new neurons), meaning it plays a key role in brain wiring and adaptation.

• Energy and blood-brain barrier (BBB) integrity. Oestrogen regulates glucose metabolism (the brain’s main energy source), boosts mitochondrial function, and helps support BBB integrity, which is crucial for healthy brain function.

• Neuroprotection. Oestrogen is a key player in protecting the brain from stress, with its anti-inflammatory actions, regulation of oxidative stress and apoptosis, and possible help in clearing buildup of toxic proteins, such as tau.

Importantly, oestrogen receptors are found in key cognitive areas like the hippocampus (important for memory), which are also sensitive to early AD development. When oestrogen drops in menopause, these supportive effects may be disrupted, helping explain why some women experience ‘brain fog’, and why menopause is being investigated as a ‘tipping point’ for brain health.

Menopause, cognitive change and AD risk

Many women notice worrying changes in cognition during menopause, with some even fearing that they are developing dementia. 

Although studies on menopause and cognition have shown mixed results, there is evidence that those in menopause transition (perimenopause) and post-menopause show changes independent of age. Neuroimaging studies have shown menopausal differences in memory-related activation patterns and AD biomarker changes such as amyloid-ß accumulation, suggesting post-menopause is associated with increased risk. It's unclear whether these changes may stem solely from shifting hormones or whether other menopause symptoms, such as sleep disruption, may contribute. Importantly, we also don’t know whether changes are permanent, or whether the brain ‘recovers’ in the years post menopause. 

"Oestrogen receptors are found in key cognitive areas like the hippocampus (important for memory), which are also sensitive to early AD development"

We do know that some groups appear to be more vulnerable. Earlier age at menopause and menopause due to surgery (surgical menopause) have been linked to increased dementia risk. Those experiencing these issues have a premature drop in hormone levels and likely less oestrogen exposure across their lives, aligning with the idea that oestrogen decline impacts risk (although, it’s important to consider underlying health issues associated with early/surgical menopause). Women at higher genetic risk for AD (those  carrying the APOEe4 gene) also show more AD-related brain changes in menopause, highlighting the importance of other factors. 

Menopause matters, but it may not be the whole story

While menopause is an important time for brain health and potential vulnerability, it is only part of a larger picture. 

Women face a complex interplay of AD risk factors. For example, the APOEe4 gene seems more harmful in women, with increased AD-relevant brain changes and risk compared with male carriers, which may be exacerbated in menopause. Cardiovascular risk, closely tied with dementia, may also increase during menopause, potentially amplifying AD risk. Additionally, mental health may also play a role, with conditions like depression more commonly diagnosed in women, and anxiety and chronic stress resulting in higher dementia risk than in men.

Social and structural factors should also be considered. Historically, women have had access to fewer educational and work opportunities, which we know is important for building cognitive reserve. Women also shoulder most of the caregiving burden, associated with higher stress and lower income. Gender inequality has even been shown to predict sex differences in cognition across countries, with larger performance gaps in countries with higher inequality. 

And of course, not all women experience risk equally; it’s critical to think about how this varies within individuals by ethnicity, socio-economic status or sexuality. Truly understanding risk involves understanding these intersecting factors, as only once we know who is at higher risk, preventions can be effectively tailored.  

Looking ahead: could HRT help protect the brain? 

Hormone Replacement Therapy (HRT) is a common treatment for menopause symptoms, replacing levels of changing hormones (usually oestrogen alone or combined with progesterone).  As this drop in hormones has been linked to brain health, could HRT help protect against future AD? 

"Earlier age at menopause and menopause due to surgery (surgical menopause) have been linked to increased dementia risk"

Thus far, this has been a controversial research area with very mixed findings. Mostly, observational studies support that HRT may be beneficial for dementia risk, but randomised controlled trials (mostly conducted with older women) suggest that HRT may have no effect, or may even increase risk. More recently, it has become clear that consideration of other factors is important too, with current beliefs indicating HRT needs to be started as close to menopause as possible (when cells are healthier) to have maximal benefits. There is also evidence that individual differences may impact how HRT impacts brain health, such as genetic risk for AD. Although there are other things to take into account, such as the fact that those seeking out HRT (as in observational studies) are usually healthier, HRT still offers promise for brain health if a holistic view is taken. 

Menopause as a window of opportunity

So, menopause may not be the missing link, but it could be an important one, offering an opportunity to identify risk and protect long-term brain health. 

AD is a major women’s health issue, and we’re only now beginning to understand how a multitude of factors intersect to influence brain ageing and dementia risk, so more female-centered research is crucial. It’s important to not just consider sex differences in risk, but also how AD develops and manifests in women to provide better prevention, diagnosis and care. Women’s brains are also important to study for their resilience, as women typically live longer, show cognitive advantage across the lifespan, and possess more cognitive reserve in later life. 

Overall, menopause may mark more than the end of fertility; it could be a turning point for long-term brain health. By understanding how hormones, genetics and social context interact, we may finally begin to close the gender gap in AD. 

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This article was written by Emily Budden and edited by Julia Dabrowska, with graphics produced by Suzana Sultan & Emily Budden. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.