P Middle aged women

I What are the effects of taking HRT

C Not taking HRT
O Risks

chrome-extension://
efaidnbmnnnibpcajpcglclefindmkaj/https://
journals.sagepub.com/doi/pdf/
10.1177/2053369119883485

chrome-extension://
efaidnbmnnnibpcajpcglclefindmkaj/https://
journals.sagepub.com/doi/pdf/
10.1177/1533317520938585
chrome-extension://
efaidnbmnnnibpcajpcglclefindmkaj/https://
journals.sagepub.com/doi/pdf/
10.1177/1755738018769925
Lejri I, Grimm A, and Eckert A. Mitochondria, estrogen
and female brain aging. Front Aging Neurosci 2018;
10: 124. Available from: www.frontiersin.org
chrome-extension://
efaidnbmnnnibpcajpcglclefindmkaj/https://
journals.sagepub.com/doi/pdf/
10.1177/17557380211035158
chrome-extension://
efaidnbmnnnibpcajpcglclefindmkaj/https://
journals.sagepub.com/doi/pdf/
10.1177/2053369119875387
chrome-extension://
efaidnbmnnnibpcajpcglclefindmkaj/https://
journals.sagepub.com/doi/pdf/
10.1177/17455057221106890
does HRT in post menopausal women increase their
risk of dementia?
chrome-extension://
gphandlahdpffmccakmbngmbjnjiiahp/https://
www.bmj.com/content/bmj/374/bmj.n2182.full.pdf

Why are women more likely to develop dementia than men?

We don't fully understand why women are more likely to

develop Alzheimer's disease than men, but one of the main
theories is to do with the hormone oestrogen.

Whilst both men and women produce oestrogen, it’s the main
female sex hormone and so women usually have more of it.
When women go through menopause, their bodies stop
producing as much oestrogen.

On the other hand, men continue to produce testosterone, the

male sex hormone, throughout their lives. Testosterone is
actually converted into oestrogen inside brain cells. This means
that women who have been through menopause have lower
levels of oestrogen in their brain than men of the same age. 

As Alzheimer's disease is more common in women after the

menopause, it is possible that oestrogen plays a role in
protecting the brain from the damage caused by Alzheimer’s,
and that this protective effect is lost when oestrogen levels are
decreased.

Oestrogen and the brain

Oestrogen affects the brain in several different ways, some of

which researchers think could help explain how it could protect
against Alzheimer's. For example, one study on rats has found
that oestrogen helps to increase the number of connections in a
particular area of the brain. This brain area, called the
hippocampus, is important for memory and certain types of
learning, which are both affected by Alzheimer's disease. 

Oestrogen can also affect the way chemicals such

as serotonin, acetylcholine and dopamine are used to send
signals throughout the brain. Some of the symptoms of
Alzheimer's disease are linked to problems with the acetylcholine
signalling system, which could be connected to decreased
oestrogen levels.

Oestrogen's protective effects

Alzheimer's is characterised by a build-up of amyloid-β and tau

proteins in the brain. Research has shown that oestrogen may
help to protect the brain from Alzheimer's by blocking some of
the harmful effects of the amyloid-β protein.

We still don't know exactly how these two proteins cause

Alzheimer's, but we think it is by causing brain cells to become
damaged or die.
One way that amyloid-β may do this is by increasing the
production of molecules inside the cells, called free radicals. Free
radicals are a normal by-product of energy production, but too
many of them can be harmful. The damage these excess free
radicals cause to brain cells has been linked to Alzheimer's.

Molecules called antioxidants act as an antidote to free radicals

by neutralising them so they are no longer harmful. Studies have
shown that higher oestrogen levels can reduce a number of free
radicals produced by cells.

Researchers think oestrogen may cause the body to make more

antioxidants, protecting brain cells from damage. This could
explain why the sudden drop in women's oestrogen levels
following menopause seems to make them more vulnerable to
Alzheimer's.
Risk factors for dementia

Understand more about risk factors for dementia with our

interactive tool.

Try our tool

Hormone replacement therapy

Some women choose to have hormone replacement therapy

(HRT) when they go through menopause to help relieve some of
the more unpleasant symptoms, such as hot flushes and mood
swings. HRT is usually a combination of oestrogen and another
hormone called progesterone, although there are different types.

Studies looking at whether replenishing oestrogen levels using

HRT can reduce women's risk of dementia have been
inconclusive and contradictory. For example, some studies of
women who were already using HRT during menopause found
that their risk of dementia was lower than those not on HRT.
However, other studies found no strong evidence for this. There
is some evidence that HRT may even increase dementia
risk. Clinical trials looking at the use of HRT to treat Alzheimer's
disease in women, rather than prevent it, did not show any
beneficial effects on cognition.

Until there is better evidence, the potential benefits of HRT as a

way to reduce the risk of Alzheimer's disease do not outweigh
the potential risks of HRT, which includes an increased risk of
certain types of cancer, heart disease and stroke.

Hormones may still provide a way to treat or prevent dementia

though. Researchers continue to look for other hormones, and
other ways of using oestrogen, which could be safer and more
effective. More research into why women are more likely to get
dementia than men is also important to help us understand
exactly what causes it.

P Middle aged WOMEN

I with low oestrogen levels
O are at a Greater risk of developing dementia
https://www.ucsf.edu/news/2011/02/98174/estrogen-therapys-
link-dementia-risk-depends-age-when-taken-study-finds
https://www.bmj.com/content/bmj/358/bmj.j3445.full.pdf
Dementia is now leading cause of death in women in England

https://www.who.int/news-room/fact-sheets/detail/dementia
Why women have more Alzheimer's disease than men: gender and mitochondrial toxicity of
amyloid-beta peptide - PubMed (nih.gov)

Why women have more Alzheimer's disease

than men: gender and mitochondrial
toxicity of amyloid-beta peptide

https://link.springer.com/content/pdf/10.1007/s12062-022-09365-
7.pdf
Can dementia become the most prevalent disease at the time of death in Germany? Projections up
to the year 2060 for the fve most important diseases at the time of deat

https://www.trinityhomecare.co.uk/resources/blog/alzheimers-
dementia/in-2020-dementia-killed-more-women-than-covid-19/
https://www.aihw.gov.au/reports/dementia/dementia-in-aus/
contents/population-health-impacts-of-dementia/deaths-due-to-
dementia
Introduction
Dementia is one of the most prevalent diseases for ageing
societies worldwide. According to the World Health
Organisation (WHO) report (2021), around 55 million people
have dementia worldwide, with over 60% living in low- and
middle-income countries. As the proportion of older people in
the population is increasing in nearly every country, this
number is expected to rise to 78 million in 2030 and 139 million
in 2050 (WHO 2021).
Dementia is a global health crisis that is escalating as
populations age. The World Health Organisation (WHO) (2021)
estimates that 55 million people worldwide are living with
dementia, with more than 60% of those people residing in low-
and middle-income countries. However, in 2030, this number is
projected to reach 78 million, and by 2050, it is expected to
reach 139 million, as the share of the world's population over
60 years of age continues to climb in practically every country
(WHO 2021).
Historically dementia has been seen as a disease of old age,
with age being the greater risk factor (2 and 4). However,
recent evidence suggests that pathophysiological changes
leading to dementia can occur up to 20 years before the
presentation of clinical symptoms, 5 and 6 which has stimulated
an urgent need to investigate how several demographic and
life-course factors influence the risk of pathologically induced
cognitive decline (3).
Dementia has long been associated with old age, and indeed,
chronological age is the strongest predictor of dementia (2 and
4). There is an urgent need to investigate how various
demographic and life-course factors influence the risk of
pathologically induced cognitive decline in light of recent
evidence suggesting that pathophysiological changes leading
to dementia can occur up to 20 years before the presentation of
clinical symptoms.5 and 6. (3).
Among the several risk factors for developing dementia,
chronological age is by far the strongest one (2 and 4). New
research suggests that the pathophysiological alterations
leading to dementia can begin up to 20 years before the onset
of clinical symptoms, highlighting the urgent need to recognise
how different demographic and life-course factors influence the
likelihood of pathologically induced cognitive decline. 5 and 6.
(3).
In particular, sex-related differences in neural anatomy is
emerging as an important factor for both the development and
treatment of dementia (2 and 7). The risk for dementia appears
to differ for men and women throughout the ageing process (8),
with women showing an increased risk for dementia shortly
after menopause (9). These findings dovetail with women
commonly reporting a ‘brain fog’ descending after menopause,
which might be the first indication of increased dementia risk.
7,10.
Scientists have found that sex-related changes in brain
anatomy are a key element in the development and treatment
of dementia (2 and 7). Men and women age differently, with
women demonstrating an increased risk for dementia after
menopause (8). (9). These findings are consistent with the fact
that women typically report experiencing "brain fog" following
menopause, which may be the first sign of an increased
dementia risk. 7,10.
Nonetheless, the relationship of menopause-induced cognitive
changes and the risk of dementia is still under exploration, with
previous studies offering conflicting findings to date. The aim of
this review is to explore the literature investigating the link
between oestrogen levels and dementia during menopause. I
shall conclude my research by outlining potential future
directions based on the reviewed evidence.
Nevertheless, research into the link between menopause and
an increased risk of dementia is still in its early stages, and past
studies have yielded mixed results to this point. The purpose of
this study is to investigate the previous research that has been
done on the subject of the correlation between oestrogen levels
and dementia during the menopause. In conclusion, I will
outline potential future courses that could be taken based on
the evidence that was evaluated.
Estrogen iswell known to have strong effects on brain
functionand integrity, in addition to its reproductive function.For
example, estrogen has been shown to have a keyrole in
regulating glucose metabolism in the brain.21Glucose
metabolism is directly linked to improved cog-nition; hence, a
reduction in the provision and potentialuptake of glucose in the
brain as a result of lower estro-gen levels might partially
account for the observedchanges in cognitive performance
post-menopause.21,22Similarly, estrogen has been shown to
have significantneurotrophic factors,23,24thereby impacting on
neuro-genesis and homeostatic brain function,25which fur-ther
highlights the role of this female sex hormone inbrain health
(Table 1).Most importantly, estrogen also functions in
themetabolism of acetylcholine, one of the main neurotrans-
mitters critical for attention and memory processes.26Hence,
the deficits, specifically in attention andmemory, post-
menopause might potentially be linked tothis hormonal-
neurotransmitter transaction, althoughsuch interactions have to
date only been shown inanimal models.25Clearly, future
investigations exploringthis role of estrogen towards
acetylcholine and cognition,in particular on a longitudinal level,
are needed to deter-mine the dynamics of the genotypic and
neurotransmitterinteractions over long time periods
In addition to its reproductive function, it is widely recognised
that oestrogen exerts powerful effects on brain function and
structure. For instance, it has been demonstrated that
oestrogen plays a crucial role in controlling glucose metabolism
in the brain. 21Glucose metabolism is directly linked to
enhanced cognition; therefore, a reduction in the supply and
possible uptake of glucose in the brain due to decreasing
estrogen levels may partially account for the reported
alterations in cognitive performance during menopause. 21,22
Similarly, oestrogen has been demonstrated to have
considerable neurotrophic factors23,24, influencing
neurogenesis and brain homeostasis25, which further
emphasises the importance of this female sex hormone to brain
health (Table 1). Moreover, oestrogen participates in the
metabolism of acetylcholine, one of the most important
neurotransmitters for attention and memory activities. 26
Postmenopausal deficiencies, particularly in attention and
memory, may therefore be related to this hormonal-
neurotransmitter connection, although such interactions have
only been demonstrated in animal models. 25 Clearly, more
longitudinal studies addressing the relationship between
oestrogen and acetylcholine and cognition are required to
determine the dynamics of the genotypic and neurotransmitter
interactions over extended time periods.
Literature review
The results, she said, “seem to confirm the critical window hypothesis.”
Women who took estrogen in mid-life but not in late life had a 26 percent
decreased risk of developing dementia in old age compared with women
who had never taken estrogen at any age, whereas women who took
estrogen in late life but not in mid-life had a 48 percent increased risk of
dementia compared with non-estrogen-taking women.

Women who took estrogen in both mid-life and late life had the same
dementia risk as women who never took it.
Yaffe, who is associate chair for clinical and translational research
in psychiatry and professor of psychiatry, neurology, and
epidemiology and biostatistics at UCSF, said she conceived the
study in an attempt to resolve contradictory evidence on the
neuroprotective effects of estrogen. “In animal models and
molecular studies, it looked as if estrogen had beneficial effects on
the brain, especially if administered early,” she said, “while at the
same time, research in humans indicated that estrogen therapy was
associated with an increased risk of dementia.”

In particular, she said, the Women’s Health Initiative, a nationwide

study funded by the National Institutes of Health, showed
significant links between estrogen therapy and dementia, as well
with as a host of other serious health problems, including breast
cancer, stroke, and cardiovascular disease.

“Nonetheless,” said Yaffe, “some scientists have wondered if the

problem with estrogen and dementia is that you have to expose
women to hormones at a certain critical period, during and just after
menopause – and that older age is too late.”

She decided to test this hypothesis, known as the “critical window

theory,” by looking at more than 40 years’ worth of data on the
Kaiser members: a health survey taken between 1964 and 1973,
when the women were middle aged; the women’s pharmacy records
from 1994 to 1998; and their patient diagnoses from 1998 to 2008.
“It was the best way I could conceive of to look at the question of
mid-life versus late-life exposure to hormone therapy,” said Yaffe,
“since no one is going to fund a 30-year trial on this question.”
Yaffe, K., Sawaya, G., Lieberburg, I. and Grady, D., 1998. Estrogen therapy in postmenopausal
women: effects on cognitive function and dementia. Jama, 279(9), pp.688-695.