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Menopause and Dementia: What is the connection?


Gayathri Delanerolle1,2, Vikram Sinai Talaulikar2, Peter Phiri1,2,4, Ashish Shetty2

1Digital Evidence Based Medicine Lab

2Southern Health NHS Foundation Trust

3University College London

4University of Southampton

Menopause is a natural process that impacts women and transgender individuals. Menopausal symptoms vary vastly although hot flushes, night sweats, sleep disturbance, mood changes and cognitive issues such as ‘brain fog’ that could impact concentration are commonly reported. For some, these symptoms are mild and short lived whilst for others these can be persistent and severe. It is unclear whether cognitive symptoms during menopausal transition indicate a future increased risk of dementia. It is vital to note that not everyone with menopause will experience significant cognitive symptoms during menopause, and the degree of cognitive impact could vary among individuals.

A link between menopause and dementia has been suggested on the basis of higher female to male ratio in affected individuals (16:10) and decline in oestrogen levels due to cessation of ovarian hormone production leading to cognitive symptoms. Observational data show an improvement in cognitive function with hormone replacement therapy started in early menopause. A late menopause appears to confer some advantage against cognitive decline in later life.

Oestrogen has neuroprotective effects and plays an important role in brain health, including cognitive function. Decrease in oestrogen levels during menopause could attribute to changes in the brain morphology and physiology, in particular alterations in brain volume linked to memory and executive function such as the prefrontal cortex and hippocampus, as well as neurotransmitters that affect sleep quality. Current research indicates that oestrogen impacts neuronal growth, synaptic plasticity and maintains the integrity of brain structures involved in memory and cognition. In addition, oestrogen also impacts the levels and function of neurotransmitters in the brain including acetylcholine, serotonin, and dopamine. These neurotransmitters play an important role in mood regulation, cognition, and memory. It is thought that fluctuations in oestrogen levels during menopausal transition can disrupt the balance of neurotransmitters impacting cognitive function in some individuals.

Another facet of menopause is its’ impact on cardiovascular health which influences vascular impediments. Oestrogen has protective effects on heart and blood vessel health and function. The endothelium (inner lining of blood vessels) plays a crucial role in production of nitric oxide, a substance that helps dilate blood vessels and regulate blood flow. During menopause, the lack of oestrogen alters endothelial function leading to reduced nitric oxide production and impaired vasodilation. This accelerates the vascular stiffness which is associated with aging process. Such changes in blood vessels can contribute to cognitive decline by reduced cerebral blood flow and oxygenation.

Menopause and declining oestrogen levels also increase the risk of small vessel disease which involves damage and dysfunction in the small blood vessels of the brain leading to formation of white matter lesions, microinfarcts and microbleeds and increased risk of vascular dementia.

Sleep disturbance, including sleep fragmentation, insomnia and night sweats as part of menopausal transition can also negatively impact cognitive processes such as memory consolidation and attention. Disrupted sleep impairs concentration and overall cognitive performance.

The ageing process increases the risk of dementia. While ageing happens side by side the changes of menopausal transition for individuals above the age of 45, it can be accelerated in conditions such as premature or early surgical menopause which are both associated with increased risk of cardiovascular and metabolic health in absence of adequate hormone replacement therapy. The relative contributions of process of ageing and menopausal decline in oestrogen need to be studied further in different age groups and causes of menopause to better understand how these independently or together affect cognitive function.

Current research in menopause and hormone replacement therapy in transgender individuals is limited. Transgender healthcare is an evolving field and better understanding of transgender individual’s experiences during menopausal transition is required. There is some evidence that transgender men taking testosterone could experience hormonal changes similar to those observed in cisgender menopausal women. Plenty more research is needed to understand the cognitive impact of hormonal changes in transgender populations. Yet another poorly researched and understood area is the association of menopause, cognitive symptoms and dementia risk across different ethnicities. Genes, dietary factors, geography/environmental factors and cultural practices/beliefs (including avoiding medical interventions) could all influence an individual’s risk of cognitive decline in relation to their ethnicity.

Genetic factors certainly play a role in the gender disparity observed in dementia. The APOE-e4 gene variant is a known risk factor for late-onset Alzheimer’s disease. Research indicates that women with the APOE-e4 gene have a higher risk of developing Alzheimer’s compared to men with the same gene variant. APOE-e4 expression has been observed at differing frequencies among different Asian, African, South Asian, and Caribbean populations. Other genes linked to dementia risk such as TOMM40 and B1NI, also exhibit gender specific effects, further contributing to the disparity.

What about the impact of HRT on risk of dementia? The effect of HRT on the risk of dementia remains unclear, with studies reporting conflicting results. Evidence from well-designed studies such as the WHI trial shows no significant improvement or worsening in memory or cognitive function with HRT in older postmenopausal women. In fact, results showed an increased risk of dementia in women who initiated combined HRT at 65-79 years of age.

The KEEPS Cognitive and Affective randomised trial which included 693 women noted no improvement or worsening in cognitive outcomes during the four-year intervention period of the study. Savolainen-Peltonen et al. (2019) reported on risk of Alzheimer’s disease with HRT in a nationwide case-control study from Finland and concluded that systemic HRT increased the risk of developing Alzheimer’s disease with both oestrogen only and combined oestrogen-progestogen. Participants under the age of 60 at the time of initiation of HRT had an increased risk of developing Alzheimer’s with exposure of more than 10 years, whilst women over the age of 60 had an increased risk of developing Alzheimer’s with any exposure. The study had number of methodological limitations.

A team of researchers from the University of East Anglia (UEA) and the University of Edinburgh found evidence of potential importance of hormone replacement therapy (HRT) in reducing risk of Alzheimer’s disease in women carrying the APOE4 gene. They analysed data from 1,178 women taking part in the European Prevention of Alzheimer’s Dementia initiative and tracked the brains of 1,906 people over 50 who did not have dementia at the start of the study. They looked at the results of cognitive tests and brain volumes as recorded by MRI scans which showed that APOE4 carriers who also used HRT had better cognition and higher brain volumes than people not on HRT and non-APOE4 carriers. The associations were particularly evident when HRT was introduced early during perimenopause.

Based on current evidence, the British Menopause Society currently recommends that women should be reassured that HRT is unlikely to increase the risk of dementia or to have a detrimental effect on cognitive function in women initiating HRT before the age of 60 and that HRT should not be initiated for the sole purpose of improving cognitive function or reducing the risk of dementia in postmenopausal women.

It is vital to note that menopause could be one factor among many which influence the risk of dementia such as lifestyle factors, genetics, and overall health status which invariably differ among ethnicities and individuals. Whilst the available evidence suggests that there could be a link between menopause and increased risk of cognitive decline in later life for some individuals, it is far from confirmatory. The current evidence related to this area stems mainly from laboratory experimental and animal studies besides some observational data. Large well controlled population studies or gold standard randomised controlled studies are lacking. It is therefore vital that scientists and healthcare professionals present the case about menopause and dementia accurately to public until further research can better identify whether lack of oestrogen at menopause indeed contributes to an increased risk and what the underlying mechanisms are.

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