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thebmj
BMJ
2019;364:l665 | doi: 10.1136/bmj.l665 1
RESEARCH
Use of postmenopausal hormone therapy and risk of Alzheimer’s
disease in Finland: nationwide case-control study
Hanna Savolainen-Peltonen,1,2 Päivi Rahkola-Soisalo,1 Fabian Hoti,3 Pia Vattulainen,3
Mika Gissler,4,5,6 Olavi Ylikorkala,1 Tomi S Mikkola1,2
ABSTRACT
OBJECTIVES
To compare the use of hormone therapy between
Finnish postmenopausal women with and without a
diagnosis for Alzheimer’s disease.
DESIGN
Nationwide case-control study.
SETTING
Finnish national population and drug register,
between 1999 and 2013.
PARTICIPANTS
All postmenopausal women (n=84 739) in Finland
who, between 1999 and 2013, received a diagnosis of
Alzheimer’s disease from a neurologist or geriatrician,
and who were identied from a national drug register.
Control women without a diagnosis (n=84 739),
matched by age and hospital district, were traced from
the Finnish national population register.
INTERVENTIONS
Data on hormone therapy use were obtained from the
Finnish national drug reimbursement register.
MAIN OUTCOME MEASURES
Odds ratios and 95% condence intervals for
Alzheimer’s disease, calculated with conditional
logistic regression analysis.
RESULTS
In 83 688 (98.8%) women, a diagnosis for Alzheimer’s
disease was made at the age of 60 years or older, and
47 239 (55.7%) women had been over 80 years of age
at diagnosis. Use of systemic hormone therapy was
associated with a 9-17% increased risk of Alzheimer’s
disease. The risk of the disease did not dier
signicantly between users of estradiol only (odds
ratio 1.09, 95% condence interval 1.05 to 1.14) and
those of oestrogen-progestogen (1.17, 1.13 to 1.21).
The risk increases in users of oestrogen-progestogen
therapy were not related to dierent progestogens
(noreth isterone acetate, medroxyprogesterone
acetate, or other progestogens); but in women
younger than 60 at hormone therapy initiation,
these risk increases were associated with hormone
therapy exposure over 10 years. Furthermore, the
age at initiation of systemic hormone therapy was
not a decisive determinant for the increase in risk
of Alzheimer’s disease. The exclusive use of vaginal
estradiol did not aect the risk of the disease (0.99,
0.96 to 1.01).
CONCLUSIONS
Long term use of systemic hormone therapy might
be accompanied with an overall increased risk of
Alzheimer’s disease, which is not related to the type
of progestogen or the age at initiation of systemic
hormone therapy. By contrast, use of vaginal estradiol
shows no such risk. Even though the absolute risk
increase for Alzheimer’s disease is small, our data
should be implemented into information for present
and future users of hormone therapy.
Introduction
Alzheimer’s disease, the most common cause of
dementia, occurs more frequently in women than in
men.1 This dierence might be due to the longer life
expectancy of women, but sex specific dierences in
the incidence of Alzheimer’s disease might also exist.1-3
It is known that oestrogens exert neuroprotection in
several animal studies.4-6 Also, oestrogen deficiency as
a result of early menopause has been associated with
an increased risk of Alzheimer’s disease.7 Therefore,
prolonging the oestrogen supply with postmenopausal
hormone therapy could protect against Alzheimer’s
disease.
However, clinical data on the association between
hormone therapy and the disease have remained
inconclusive. Despite several observational studies
supporting the protective eect of hormone therapy
on Alzheimer’s disease,8-13 a subsequent placebo
controlled trial (the Women’s Health Initiative Memory
Study (WHIMS)) failed to confirm this benefit, and
in fact implied an increased risk of overall dementia
in hormone therapy users.14 15 The conflicting data
could in part result from dierences in the study
design, study populations, or hormone therapy
regimens. Unlike clinical practice, hormone therapy
in the WHIMS trial was initiated in women aged 65
or older.14 15 Thus, one explanation might also be the
timing hypothesis, which suggests that oestrogen
WHAT IS ALREADY KNOWN ON THIS TOPIC
Data on the association between use of postmenopausal hormone therapy and
risk of Alzheimer’s disease are conflicting
Several observational studies have indicated that hormone therapy might have a
protective eect on the risk of Alzheimer’s disease, but this was not supported by
the placebo controlled Women’s Health Initiative Memory Study
These ndings were later challenged by the timing hypothesis, which indicates
that oestrogen could be neuroprotective only if it is started soon aer the onset
of menopause
WHAT THIS STUDY ADDS
Use of postmenopausal systemic hormone therapy is accompanied with an
increase in the risk of Alzheimer’s disease in postmenopausal women, whereas
the use of vaginal estradiol shows no such risk
Particularly long term exposure to hormone therapy is associated with an
increased risk of Alzheimer’s disease, but the increase in risk is not dependent
on the age at treatment initiation
1University of Helsinki and
Helsinki University Hospital,
Obstetrics and Gynecology,
Haartmaninkatu 2, PO Box
140, FIN-00029 HUS, 00029
Helsinki, Finland
2Folkhälsan Research Center,
Biomedicum, Helsinki, Finland
3EPID Research Oy, Espoo,
Finland
4National Institute for Health
and Welfare, Helsinki, Finland
5Karolinska Institute,
Department of Neurobiology,
Care Sciences and Society,
Division of Family Medicine,
Huddinge, Sweden
6University of Turku, Research
Centre for Child Psychiatry,
Turku, Finland
Correspondence to: T S Mikkola
tomi.mikkola@hus.
(ORCID 0000-0003-2049-088X)
Additional material is published
online only. To view please visit
the journal online.
Cite this as: BMJ 2019;364:l665
http://dx.doi.org/10.1136/bmj.l665
Accepted: 1 February 2019
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BMJ
2019;364:l665 | thebmj
could be neuroprotective only if started soon after the
onset of menopause.16 This hypothesis originates from
cardiovascular studies17 where the age at the start of
hormone therapy appears to predict the cardiovascular
eects of hormone therapy. Treatment initiated before
age 60 is protective, but if started at a later age, it is
detrimental towards the vasculature. Such a window
for hormone therapy use has also been suggested for
cognitive eects.16
By using Finnish comprehensive nationwide
registers, we were able to conduct a case-control
comparison to investigate whether hormone therapy
had an eect on the risk of Alzheimer’s disease, and
whether this risk was associated with age of treatment
initiation or duration of treatment use.
Methods
In Finland, patients with Alzheimer’s disease
are entitled to 40% reimbursement for treatment
from national health insurance, but this requires a
statement from a neurologist or geriatrician. They must
base the diagnosis on symptoms consistent of mild
or moderate Alzheimer’s disease, decrease in social
capacity for at least three months, cognitive tests,
magnetic resonance imaging or computed tomography
scanning of the brain, and exclusion of alternative
diagnoses. The physician also must confirm whether
the patient has other dementia related diseases, such
as Lewy body dementia or mixed dementia. For mixed
dementia, patients are entitled to reimbursement only
if the symptoms and findings are caused mainly by
Alzheimer’s disease. In total, 84 739 women with a
diagnosis for Alzheimer’s disease were entered into this
register in 1999-2013. During the same period of time,
control women without a diagnosis were identified
from the Finnish National population register (one
control per case; n=84 739). Control women were
matched with cases by age (within 1 month) and by
hospital district according to the woman’s municipality
of residence. Hospital districts were further divided
into five university hospital districts.
Finland has a reliable nationwide register that
includes all hormone therapy users from year 1994.
Use of the treatment in Finland is available only
with a physician’s prescription, and regimens are
partly (40-60%) reimbursed by the government. At
each pharmacy visit, hormone therapy purchases
are entered into the drug reimbursement register,
confirming use of the prescribed regimen of hormone
therapy. The register was initiated in 1994, so we could
not dierentiate whether a woman who bought the
treatment in 1994 was a new user or was continuing
her treatment initiated before 1994. Therefore, we
assumed that all systemic users older than 52 years in
1994 had initiated the treatment at age 52 and vaginal
users at age 65, which are the mean ages at systemic
and vaginal initiation of hormone therapy in our study
population, respectively.18 This approximation has
been used in several previous studies. 19-21 However,
we also analysed separately women who had started
hormone therapy in 1995 (one year after the register
opened) or later (that is, fresh starters: 65 102 cases
and 65 102 controls), because this group’s detailed
history of treatment use was documented in the
register. The findings in this subanalysis were fully in
line with those in the whole study population, so the
data of this subanalysis are not shown.
The regimens of systemic hormone therapy in
Finland contain exclusively estradiol, which is given
either orally (90%) or transdermally (10%). The
regimens identified by trade names were transformed
into doses of estradiol (oral or transdermal). Various
progestogens were used in combination with estradiol
(that is, oestrogen-progestogen therapy), of which
norethisterone acetate and medroxyprogesterone
acetate were the most common.20 According to the
Finnish guidelines, only women who have had
hysterectomies can use estradiol without progestogen,
and these women were studied as an estradiol only
group. Oral estradiol doses in Finland are usually 1-2
mg/day, and transdermal (gel or patch) estradiol is
used with equivalent doses (25-100 μg/day). However,
owing to the switching of the use of hormone therapy
from one route to another and to the relatively similar
route independent levels of circulating oestrogen, we
did no subanalyses according to the treatment route.
Sequential users of oestrogen-progestogen therapy
were defined as women who used estradiol with 10-
14 days of progestogen courses each month, or at
intervals of one to three months. Women who used both
estradiol and progestogen every day were considered
as continuous users of oestrogen-progestogen therapy.
Tibolone users were considered as a separate group.
Users of vaginal estradiol only (Vagifem, NovoNordisk,
Copenhagen, Denmark; 25 μg twice a week) were
analysed separately.
Exposure to hormone therapy (ever use) was
considered to have started from the date of the
first purchase, or from age 52 if systemic hormone
therapy was used at the register opening or from
age 65 years if vaginal estradiol was used at register
opening. Cumulative exposure to hormone therapy
was classified by duration (lasting ≤3 years, >3 to ≤5
years, >5 to ≤10 years, or >10 years). We assessed the
time period from treatment initiation to diagnosis for
Alzheimer’s disease. To address the potential critical
time window for oestrogen brain eect,16 we also
compared the risk of the disease in women who had
started hormone therapy aged under 60 versus those
aged 60 and over.
Statistical methods
We used a conditional logistic regression analysis to
estimate, by using odds ratios with 95% confidence
intervals, the relative risk of Alzheimer’s disease
associated with dierent regimens of hormone therapy.
The association between age at treatment initiation
and Alzheimer’s disease was also analysed with
conditional logistic regression, using both continuous
age and five years age classes as variables. We used
the χ2 test to test dierences between categorical
variables. Dierences between continuous variables
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RESEARCH
thebmj
BMJ
2019;364:l665 | doi: 10.1136/bmj.l665 3
were evaluated with the student’s t test or two tailed
test of equal or given proportions. Significance was set
at P<0.05.
Patient and public involvement
No patients were involved in the setting of the
research question or the outcome measures, nor were
they involved in the developing plans for design or
implementation of the study. No patients were asked
to advise on interpretation or writing up of the results.
There are no plans to disseminate the results of the
research to study participants or the relevant patient
community.
Results
Overall, in 83 688 (98.8%) women, a diagnosis for
Alzheimer’s disease was made at the age of 60 years
or older, and 47 239 (55.7%) women had been over 80
years of age at diagnosis (table 1). Time from initiation
of hormone therapy to diagnosis was shorter than five
years in 886 (5.6%) women, but longer than 10 years
in 11 805 (74.9%). At the time of diagnosis, only 2305
(14.6%) women were still using hormone therapy,
whereas 10 188 (64.6%) had stopped treatment more
than three years before diagnosis.
Patients with Alzheimer’s disease used systemic
hormone therapy more often (18.6% v 17.0%,
respectively, P<0.001) but used vaginal estradiol only
less often (12.7% v 13.2%, P=0.005) than controls (table
1). The mean exposure time to systemic hormone therapy
did not dier between patients with Alzheimer’s disease
and control women (table1). The relative proportions of
dierent progestogens users were similar in cases and
controls (table 1), but exposure to oestrogen-progestogen
therapy with other or mixed progestogens was longer in
patients with Alzheimer’s disease (P=0.02).
Overall, hormone therapy users with Alzheimer’s
disease (n=11 456, 73.7%) had started systemic
hormone therapy under age 60 years less often than
controls (n=10 662, 75.1%, P=0.006). The mean age
at initiation of estradiol only was similar for patients
with Alzheimer’s disease and controls (table 1), but
the mean age at initiation of oestrogen-progestogen
therapy was slightly higher for patients with
Alzheimer’s disease than for controls (56.1 (standard
deviation 7.8) v 55.8 (7.6), P=0.02).
Table1 | Characteristics of study population. Data are number (%) of women unless stated otherwise
Patients with Alzheimer’s disease (n=84 739) Controls (n=84 739) P
Start of follow-up (age at Alzheimer diagnosis (years) for cases)
<50 99 (0.1) 101 (0.1) —
50-54 273 (0.3) 274 (0.3) —
55-59 679 (0.8) 678 (0.8) —
60-64 1373 (1.6) 1373 (1.6) —
65-69 4028 (4.8) 4028 (4.7) —
70-74 10 731 (12.7) 10 785 (12.7) —
75-79 20 317 (24.0) 20 311 (24.0) —
≥80 47 239 (55.7) 47 193 (55.7) —
University healthcare district at the time of diagnosis
Northern (Oulu) 14 794 (17.5) 14 746 (17.4) —
Eastern (Kuopio) 17 425 (20.6) 17 450 (20.6) —
Southern (Helsinki) 24 053 (28.4) 23 956 (28.3) —
Western (Turku) 10 856 (12.8) 10 873 (12.8) —
Central Finland (Tampere) 17 574 (20.7) 17 624 (20.8) —
Unknown 6 (0.01) 3 (0.0) —
Abroad 31 (0.04) 87 (0.1) —
Hormone therapy use
No use 58 186 (68.7) 59 175 (69.8) <0.001
Systemic use 15 768 (18.6) 14 394 (17.0)
Estradiol only 5606 (35.6) 5312 (36.9) 0.01
EPT 9941 (63.0) 8890 (61.9)
EPT with MPA 1955 (19.7) 1795 (20.1) 0.27
EPT with NETA 3080 (31.0) 2661 (29.8)
EPT with other* or mixed progestogens 4906 (49.4) 4434 (50.0)
Tibolone 221 (1.4) 192 (1.3) 0.17
Vaginal estradiol 10 785 (12.7) 11 170 (13.2) 0.005
Age at hormone therapy initiation (mean, SD)
Estradiol only 58.0 (9.3) 57.7 (9.0) 0.1
EPT 56.1 (7.8) 55.8 (7.6) 0.02
Exposure time (mean, SD)
Systemic use 11.4 (8.6) 11.5 (8.6) 0.19
Estradiol only 11.8 (9.3) 11.9 (9.4) 0.40
EPT 9.8 (7.7) 9.7 (7.7) 0.28
EPT with MPA 9.6 (7.9) 9.7 (7.7) 0.10
EPT with NETA 7.0 (7.4) 6.7 (7.3) 0.28
EPT with other* or mixed progestogens 11.6 (7.4) 11.3 (7.4) 0.02
Tibolone 1.6 (1.8) 1.6 (1.7) 0.93
EPT=oestrogen-progestogen therapy; NETA=norethisterone acetate; MPA=medroxyprogesterone acetate; SD=standard deviation.
*Other progestogens include levonorgestrel, progesterone, megestrol acetate, lynestrenol, drospirenone, and trimegestone.
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4 doi: 10.1136/bmj.l665 |
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2019;364:l665 | thebmj
In the whole study population, the risk of Alzheimer’s
disease was increased but did not dier significantly
between users of estradiol only (odds ratio 1.09, 95%
confidence interval 1.05 to 1.14) and those of oestrogen-
progestogen (1.17, 1.13 to 1.21). Exclusive use of
vaginal estradiol was not related to risk of Alzheimer’s
disease (0.99, 0.96 to 1.01). In women younger than
60 at hormone therapy initiation, use of the dierent
oestrogen-progestogen therapies was associated with
an 8-17% increased risk of Alzheimer’s disease (table
2). We saw no significant dierences between the
dierent therapies with regards to Alzheimer’s disease
risk. Use of estradiol only was associated with a small
but significant increase in disease risk. The risk of
Alzheimer’s disease in estradiol only users (odds ratio
1.06, 95% confidence interval 1.01 to 1.12) and all
users of oestrogen-progestogen therapy (1.14, 1.09 to
1.19) did not dier significantly. The use of tibolone
carried no significant risk of Alzheimer’s disease in
this age group. The risk increases in users of estradiol
only and oestrogen-progestogen therapy were related
to 10 years of exposure or more, whereas shorter use of
hormone therapy was not associated with Alzheimer’s
disease risk (table 3).
In women aged 60 or older at the initiation of
hormone therapy, use of estradiol only, oestrogen-
progestogen therapy, or tibolone was associated with
similar increases in risk (15-38%) for Alzheimer’s
Table2 | Odds ratios for Alzheimer’s disease in women younger than 60 or aged 60 and older at treatment initiation of
estradiol only or various combined therapies
Age at initiation and type of hormone therapy Patients with Alzheimer’s disease (No) Controls (No) Odds ratio (95% CI) P
Age <60 years
No hormone therapy 48 331 48 925 1.00 —
Estradiol only 3125 3042 1.06 (1.01 to 1.12) 0.03
EPT 6330 5812 1.14 (1.09 to 1.19) <0.005
EPT with MPA 1296 1247 1.08 (1.00 to 1.17) 0.06
EPT with NETA 1419 1270 1.17 (1.08 to 1.26) <0.005
EPT with other* or mixed progestogens 3615 3295 1.15 (1.09 to 1.21) <0.005
Tibolone 83 90 0.97 (0.72 to 1.32) 0.86
Age ≥60 years
No hormone therapy 45 180 45 635 1.00 —
Estradiol only 1310 1157 1.15 (1.06 to 1.25) <0.005
EPT 1630 1352 1.23 (1.14 to 1.32) <0.005
EPT with MPA 269 227 1.21 (1.01 to 1.44) 0.04
EPT with NETA 963 792 1.23 (1.12 to 1.36) <0.005
EPT with other* or mixed progestogens 398 333 1.21 (1.05 to 1.41) 0.009
Tibolone 90 66 1.38 (1.00 to 1.89) 0.05
EPT=oestrogen-progestogen therapy; NETA=norethisterone acetate; MPA=medroxyprogesterone acetate.
*Other progestogens include levonorgestrel, progesterone, megestrol acetate, lynestrenol, drospirenone, and trimegestone.
Table3 | Odds ratios for Alzheimer’s disease in women younger than 60 or aged 60 and over at treatment initiation of
estradiol only or various combined therapies, stratied by duration of treatment
Type and duration of hormone therapy Patients with Alzheimer’s disease (No) Controls (No) Odds ratio (95% CI) P
Age <60 years at treatment initiation
Estradiol only
No hormone therapy 44 879 44 978 1.00 —
<3 years 126 140 0.89 (0.69 to 1.15) 0.38
3 to <5 years 78 60 1.31 (0.93 to 1.87) 0.13
5 to <10 years 254 286 0.88 (0.74 to 1.06) 0.18
≥10 years 1989 1862 1.07 (1.00 to 1.15) 0.04
Oestrogen-progestogen therapy
No hormone therapy 46 301 46 796 1.00 —
<3 years 845 854 1.02 (0.92 to 1.13) 0.67
3 to <5 years 401 416 1.00 (0.86 to 1.15) 0.98
5 to <10 years 1118 1063 1.10 (1.00 to 1.20) 0.05
≥10 years 3355 2891 1.20 (1.13 to 1.26) <0.005
Age ≥60 years at treatment initiation
Estradiol only
No hormone therapy 43 894 44 062 1.00 —
<3 years 905 804 1.13 (1.03 to 1.25) 0.01
3 to <5 years 160 119 1.35 (1.07 to 1.72) 0.01
5 to <10 years 164 139 1.19 (0.95 to 1.50) 0.13
≥10 years 28 27 1.04 (0.61 to 1.77) 0.88
Oestrogen-progestogen therapy
No hormone therapy 44 135 44 422 1.00 —
<3 years 1204 1015 1.20 (1.10 to 1.30) <0.005
3 to <5 years 233 179 1.32 (1.08 to 1.60) 0.006
5 to <10 years 198 147 1.36 (1.10 to 1.69) <0.005
≥10 years 17 24 0.73 (0.39 to 1.35) 0.31
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2019;364:l665 | doi: 10.1136/bmj.l665 5
disease (table 2). In this age group, the increased risk
was already detectable after three to five years’ use
of estradiol only or oestrogen-progestogen therapy
(table 3). The increases in risk of Alzheimer’s disease
between women younger than 60 and those aged 60 or
older at treatment initiation did not dier significantly.
When the eect of age at treatment initiation on
risk of Alzheimer’s disease was analysed further in
five year intervals, no association emerged (fig 1).
Furthermore, age as a continuous variable was no
determinant for disease risk in users of estradiol only
(odds ratio 1.0, 95% confidence interval 0.98 to 1.02),
oestrogen-progestogen therapy (1.0, 0.99 to 1.01), or
any hormone therapy (1.0, 0.99 to 1.01). The disease
appeared earlier in women with a history of systemic
use of hormone therapy than in those with vaginal
estradiol use or without any prior use of the treatment
(fig 2).
Discussion
Principal ndings
In our large case-control study of 84 739 patients with
Alzheimer’s disease and a similar number of control
women, we showed that the systemic use of estradiol
only or oestrogen-progestogen therapy was associated
with an increased risk of Alzheimer’s disease, whereas
use of vaginal estradiol showed no such risk. The age
at initiation of hormone therapy did not appear to be a
determinant for risk of the disease, whereas in women
younger than 60 at treatment initiation, the risk
increases were associated with exposure to hormone
therapy for over 10 years.
Comparison with other studies
Most observational studies have reported a reduced
risk of Alzheimer’s disease and all cause dementia in
users of hormone therapy.8-13 22 These analyses can be
criticised, owing to the lack of a placebo arm and the
possible bias of healthy woman in hormone therapy
users. This criticism gained strong support from the
placebo controlled WHIMS trial, reporting an increased
risk of impaired cognition and probable dementia in
women who used conjugated equine oestrogens (CEE)
with and without medroxyprogesterone acetate.14 15
On the other hand, this study was also criticised
because, unlike in normal clinical practice, hormone
therapy was initiated for women older than 65, many
years after the onset of menopause. Moreover, the
WHIMS study did not dierentiate Alzheimer’s disease
from other dementia or cognitive decline, although
the pathophysiology of dementia includes multiple
dierent neurodegenerative and vascular processes,
which could respond dierently to oestrogen exposure.
Our epidemiological study, although large in size
and conducted in a case-control setting, can show
only associations between hormone therapy use and
the risk of Alzheimer’s disease. Moreover, the small
risk increases are vulnerable to bias from unsuspected
sources, which are unavoidable in all observational
studies.8-13 But if there is a causal relation, it seems
that estradiol could be primarily responsible for the
increased risk of Alzheimer’s disease, because use
of estradiol only was related to the increased risk.
However, progestogen could potentiate the eect of
estradiol on the risk of Alzheimer’s disease, because the
risk elevations tended to be higher in users of oestrogen-
progestogen therapy than users of estradiol only. This
notion accords with the WHIMS study finding14 15 that
the risk of all cause dementia was higher in users of CEE
and medroxyprogesterone acetate than in those using
CEE only. Progestogens, such as medroxyprogesterone
acetate or norethisterone acetate, dier in structure
and in their capacity to bind to progesterone and other
steroid hormone receptors23; therefore, the risk of
Alzheimer’s disease in users of the dierent oestrogen-
progestogen therapies could vary. Our data show
that norethisterone acetate, medroxyprogesterone
acetate, or other progestogens as components of
oestrogen-progestogen therapy do not dier in regard
to risk of Alzheimer’s disease. Tibolone, a synthetic
steroid hormone with oestrogenic, progestogenic,
and androgenic actions, has shown a neuroprotective
eect in preclinical studies.24 Our finding implies that
tibolone does not dierentiate significantly from other
forms of systemic hormone therapy with regard to the
risk of Alzheimer’s disease, but owing to the small
number of tibolone users, this conclusion must be
interpreted with caution.
The cause of Alzheimer’s disease is not yet fully
understood, but β amyloid plaques and neurofibrillary
tangles containing hyperphosphorylated τ protein
do accumulate in the brain. 25 26 Several risk factors,
such as genetic tendency, head trauma, smoking, and
low education could speed up the development of the
disease. Multiple full term pregnancies might also
predispose to the development of Alzheimer’s disease,
perhaps due to repeat oestrogen and progesterone
surges.27 Our present data imply that the prolongation
of estradiol exposure beyond the natural menopausal
age with the use of hormone therapy could stimulate
the progression of Alzheimer’s disease, and thus
increase its risk, especially if such exposure to estradiol
is continued for over 10 years. Our data do not allow
any detailed speculations for the possible biological
Age at
initiation
of any HT
75-79
70-74
65-69
60-64
55-59
<50-54
00.5 1.51.0
Odds ratio
(95% CI)
47/60
134/130
260/277
343/305
358/365
3570/3579
No of cases
/controls
Fig1 | Risk of Alzheimer’s disease in women initiating systemic hormone therapy (HT) at
dierent ages, as odds ratios and 95% condence intervals. Line at 1.0 denotes the risk
in the group of women who started systemic use younger than 55. Numbers of cases
and controls are given for ve years periods
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mechanism through which estradiol could have
caused this eect. Although estradiol might inhibit
the accumulation of β amyloid in animal models and
in early postmenopausal women,3 6 28 it has been
speculated that such an eect of oestrogen is lost
with advancing age. We sought thoroughly for such a
timing eect from our data, but we must conclude that
the age at initiation of hormone therapy is no decisive
determinant for the risk of Alzheimer’s disease in the
future.
We have previously shown that the systemic use of
estradiol based hormone therapy was associated with
a marked dierence in the death risk of dementia; the
risk of death for vascular dementia was profoundly
decreased (by 37-39%), whereas risk of death
for Alzheimer’s disease showed a much smaller
decrease or even lacked a decrease. 21 Furthermore,
in the extended follow-up of the Women’s Health
Initiative study,29 the mortality for Alzheimer’s
disease and other dementia was reduced in CEE
users, although the authors conclude that this finding
should be interpreted cautiously because of multiple
comparisons. It is possible that the use of hormone
therapy is accompanied, directly or indirectly, with a
decreased risk of the most severe forms of Alzheimer’s
disease, perhaps by improving cardiovascular health.
Yet, it is the incidence of and not mortality from
Alzheimer’s disease that determines the total burden
of the disease.
Strengths and limitations of the study
Our study had several limitations. Firstly, we did
not have baseline demographic data for known risk
factors for Alzheimer’s disease, either for the hormone
therapy users or controls. We would not expect this
omission to cause many errors in our study, because
several common dementia risk factors (hypertension,
hypercholesterolaemia, and smoking) were evenly
distributed between the two groups in another study
from the same population.30 Moreover, cardiovascular
mortality was reduced in the Finnish hormone
therapy users,18 20 implying that higher cardiovascular
morbidity could not explain the elevated disease risk
of hormone therapy users in our study. The ApoE
E4 allele frequency in Finland (at nearly 20%) is
among the highest in the world,31 32 and some studies
suggest that the eects of postmenopausal hormone
therapy on Alzheimer’s disease are modified by the
ApoE status.2 ApoE E4 is not screened in the Finnish
healthcare system, but it is unlikely that ApoE status
would have diered between the two study groups.
Furthermore, Finnish users of hormone therapy did
not dier in socioeconomic status or education from
the non-users,33 and healthcare services in Finland are
available for everyone, free of charge, or substantially
subsidised.
Secondly, due to the first signs of cognitive
impairment seven to eight years before the final
diagnosis,34 there is a possibility that such women
sought help from hormone therapy, and thus an
increased risk of Alzheimer’s disease was a cause for
its use and not its consequence. However, this seems
unlikely in our population, because the disease
diagnosed most often at over age 80 would have
caused symptoms at around age 72-7334; however,
most hormone therapy users (74%) started use under
age 60. Furthermore, only 14% of users were still on
hormone therapy at the time of diagnosis. Thirdly,
the duration of the pre-register use of hormone
therapy had to be estimated in a quarter of the total
study population. However, based on the previous
data,20 21 such an estimation for hormone therapy
use is accurate. Fourthly, controls were not screened
with magnetic resonance imaging of the brain or
neurological examination to exclude Alzheimer’s
disease, and thus some controls could have had
undiagnosed disease. This chance should not cause
any concern because the prevalence of Alzheimer’s
disease in Europe is 4.4%.35 Finally, although we could
reliably dierentiate between systemic and vaginal use
of estradiol, we were not able to compare the use of
oral and transdermal preparations with use of cyclic
and continuous oestrogen-progestogen therapy.
Our study also had several strengths. Firstly, this
study is one of the largest on the association between
hormone therapy and Alzheimer’s disease. Secondly,
it is vital that in a study on women with cognitive
decline, the use of hormone therapy was objectively
assessed from a reliable nationwide register controlled
by authorities, because self reporting is not reliable
in patients with poor cognitive performance. Thirdly,
Alzheimer’s disease was accurately diagnosed and
dierentiated from vascular dementia and other
forms of dementia or cognitive decline according to
internationally approved criteria.36 Finally, it has been
shown that 97% of Finnish patients with Alzheimer’s
disease actually use treatment37 and thus have been
included into the reimbursement register, which
confirms that we could reliably detect patients with
Alzheimer’s disease in Finland.
Conclusions and policy implications
The present study indicates that the use of systemic
hormone therapy, once claimed to be protective against
Alzheimer’s disease, is accompanied with a 9-17%
Age group
Proportion with diagnosis
of Alzheimer's disease (%)
0
20
30
40
10
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90-94
95-99
≥100
No HT
Any HT
Vaginal use of estradiol
Fig2 | Proportion (%) of women with a diagnosis of Alzheimer’s disease in dierent
age groups according to systemic use of hormone therapy, vaginal use of estradiol, or
without any history of hormone therapy (HT) use
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thebmj
BMJ
2019;364:l665 | doi: 10.1136/bmj.l665 7
increase in the risk of the disease in postmenopausal
women, whereas the exclusive use of vaginal estradiol
shows no risk. In absolute terms, we estimate that nine
to 18 excess diagnoses of the disease per year will be
detected in 10 000 women aged 70-80 (incidence 105
per 10 000 women years in this age group), especially
in those who had used hormone therapy for over 10
years. The age at initiation of hormone therapy is no
decisive determinant for the future risk of Alzheimer’s
disease. Hormone therapy users should be informed
for a possible risk of the disease with prolonged use
of Alzheimer’s disease, even though the absolute risk
elevations are small.
Contributors: TSM and OY designed the study. FH, PV, and MG
analysed the data. HS-P draed the gure and the tables. HS-P, PR-S,
OY, and TSM draed the manuscript, and all the authors read, revised
the manuscript, and approved its nal version. TSM and HS-P are
responsible for the overall content as guarantors, and accept full
responsibility for the work and the conduct of the study, had access
to the data, and controlled the decision to publish. The corresponding
author attests that all listed authors meet authorship criteria and that
no others meeting the criteria have been omitted, had full access to all
the data in the study, and had nal responsibility for the decision to
submit for publication.
Funding: This study was supported by a Helsinki University Hospital
research grant and the Jane and Aatos Erkko Foundation. The funders
had no role in the study design; in the collection, analysis, and
interpretation of data; in the writing of the report; and in the decision
to submit the article for publication. We conrm that the researchers
were independent from funders and that all authors had full access
to all of the data (including statistical reports and tables) in the
study and can take responsibility for the integrity of the data and the
accuracy of the data analysis.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf and declare:
support from Helsinki University Hospital and the Jane and Aatos
Erkko Foundation for the submitted work; speaker and consulting fees
for Mylan (HS-P, TSM) and Astellas (TSM); funding for congress trips
from Merck, Sharp, and Dohme (HS-P), Astellas (PR-S), and Olympus
(PR-S); FH and PV work for EPID Research, which performs nancially
supported studies for several pharmaceutical companies; no other
relationships or activities that could appear to have influenced the
submitted work.
Ethical approval: The research committee of the Helsinki University
Hospital approved our study plan. Approval from the ethics
committee was not needed in our register based study because we
did not contact any study patients or their care givers. Appropriate
approvals for the use of condential register data in scientic research
were obtained from the National Institute for Health and Welfare
(THL/1370/5.05.00/2010), Statistics Finland (TK-53-1560-10), and
the Social Insurance Institution of Finland (KELA 40/522/2010). All
data were pseudonymised before inclusion into the study database.
Data sharing: No additional data are available.
The lead author arms that the manuscript is an honest, accurate,
and transparent account of the study being reported; that no
important aspects of the study have been omitted; and that any
discrepancies from the study as originally planned (and, if relevant,
registered) have been explained.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on dierent
terms, provided the original work is properly cited and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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