Postmenopausal hormone therapy and

Alzheimer disease
A prospective cohort study

Bushra Imtiaz, MD, ABSTRACT

MPH Objective: To explore the association between postmenopausal hormone therapy (HT) and Alz-
Marjo Tuppurainen, MD, heimer disease (AD).
PhD
Methods: Twenty-year follow-up data from the Kuopio Osteoporosis Risk Factor and Prevention
Toni Rikkonen, PhD
study cohort were used. Self-administered questionnaires were sent to all women aged 4756
Miia Kivipelto, MD, PhD
years, residing in Kuopio Province starting in 1989 until 2009, every 5th year. Register-based
Hilkka Soininen, MD,
information on HT prescriptions was available since 1995. Probable AD cases, based on DSM-IV
PhD
and National Institute of Neurological and Communicative Disorders and StrokeAlzheimers
Heikki Krger, MD, PhD
Disease and Related Disorders Association criteria, were identified from the special reim-
Anna-Maija Tolppanen,
bursement register (19992009). The study population included 8,195 women (227 cases of
PhD
incident AD).
Results: Postmenopausal estrogen use was not associated with AD risk in register-based or self-
Correspondence to reported data (hazard ratio/95% confidence interval 0.92/0.681.2, 0.99/0.751.3, respec-
Dr. Imtiaz: tively). Long-term self-reported postmenopausal HT was associated with reduced AD risk
bushra.imtiaz@uef.fi
(0.53/0.310.91). Similar results were obtained with any dementia diagnosis in the hospital
discharge register as an outcome.
Conclusions: Our results do not provide strong evidence for a protective association between
postmenopausal HT use and AD or dementia, although we observed a reduced AD risk among
those with long-term self-reported HT use. Neurology 2017;88:10621068

GLOSSARY
AD 5 Alzheimer disease; BMI 5 body mass index; CEE 5 conjugated equine estrogen; DSM-IV 5 Diagnostic and Statistical
Manual of Mental Disorders, 4th edition; HT 5 hormone therapy; ICD-10 5 International Classification of Diseases10;
MPA 5 medroxyprogesterone acetate; SII 5 Social Insurance Institution; WHIMS 5 Womens Health Initiative Memory Study.

Alzheimer disease (AD), the most common form of dementia, accounts for 60%80% of cases.1
Women have AD more often than men either due to their increased life expectancy2,3 or decline
in sex steroid hormone levels around menopause,1,4 although some small studies have not
detected this sex difference.5,6 Neuroprotective effects of estrogen have been observed in exper-
imental animals,710 but clinical trials on postmenopausal hormone therapy (HT) use have not
been successful,1113 including the largest clinical trial to date, the Womens Health Initiative
Memory Study (WHIMS).14 Observational studies support use of HT against AD if initiated
around menopause in some15,16 but not all studies.1720 Similarly, register-based studies have
yielded conflicting results.18,20,21 Results from the Leisure World cohort revealed that the
reduced risk of AD among HT users was a function of dose and duration.22,23
Supplemental data
at Neurology.org
From the Institute of Clinical MedicineNeurology (B.I., M.K., H.S.), Kuopio Musculoskeletal Research Unit, Clinical Research Center (M.T.,
T.R., H.K.), and Research Center for Comparative Effectiveness and Patient Safety (RECEPS) and School of Pharmacy (A.M.T.), University of
Eastern Finland, Kuopio; Department of Obstetrics and Gynecology (M.T.), Neurocenter, Neurology (H.S.), and Department of Orthopedics and
Traumatology (H.K.), Kuopio University Hospital, Finland; Department of Medicine (T.R.), University of Cambridge, UK; and Division of
Clinical Geriatrics (M.K.), Center for Alzheimer Research, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
The views expressed in this article are solely of the authors and not of any funding body. The funders had no role in data collection, management,
analysis, interpretation, or review of the manuscript.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
The Article Processing Charge was paid by the authors.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC
BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used
commercially without permission from the journal.

1062 Copyright 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
 The aim of our study is to investigate the systematically evaluates the diagnostic evidence for each AD case
and confirms whether the prespecified criteria are met excluding
association of self-reported and register-
possible alternative diagnoses for memory impairment such as
recorded postmenopausal HT use with AD severe depression, metabolic disturbances, and other forms of
in a longitudinal prospective cohort, while tak- dementia such as vascular dementia without AD-like symptoms.
ing into account various socioeconomic and We also performed sensitivity analyses with dementia as an
outcome. These data were extracted from the National Hospital
lifestyle-related AD risk factors. Discharge register using the following ICD-10 codes: F00F03
(F00, dementia in Alzheimer disease; F01, vascular dementia;
METHODS Study population. The present study is based on F02, dementia in other diseases classified elsewhere; F03, unspec-
the 20-year follow-up of the population of the Kuopio ified dementia) and G30 (Alzheimer disease, early/late onset).
Osteoporosis Risk Factor and Prevention study cohort. A self- This register includes all inpatient admissions. Diagnosis codes
administered baseline postal questionnaire was sent to all for each admission are recorded by attending physician. All
women aged 4756 years who were residents of Kuopio Finnish citizens/long-term residents are covered by tax-supported
Province, Eastern Finland (n 5 14,220), in February 1989. A public health service.
total of 13,100 (92.1%) women responded. The reasons for
nonresponse were lack of address or residence not detected (n 5 Use of HT. Self-reported HT use was recorded as lifetime use in
119) and death (n 5 4). In addition, 947 women did not respond years (and indication of use) at the baseline inquiry in 1989. In all
for other reasons and 50 returned a blank form. The 5-year follow- follow-up questionnaires, numbers of months per year of estrogen
up in 1994, 10-year follow-up in 1999, 15-year follow-up in use were reported and the duration of self-reported estrogen use
2004, and 20-year follow-up in 2009 was mailed to the 13,100, was calculated on basis of these questionnaires. Current
12,562, 12,075, and 11,420 women, respectively. A total of medication prescribed by a physician, duration and purpose of
11,954 (91.2%), 11,538 (91.8%), 10,926 (90.4%), and 8,195 use, and name of tablets used were asked in all inquiries. To
(71.8%) women responded to the 5-, 10-, 15-, and 20-year follow- exclude the possibility of recall bias in the self-reported
ups, respectively. The questionnaires were sent to women who had questionnaires, we accessed the prescription register data to
responded to the baseline inquiry, were alive, and had a valid ascertain HT use. Vaginal products were excluded. HT was
postal address at that time. defined from the registry as those preparations having systemic
The baseline questionnaire covered demographics, lifestyle, estrogenic properties belonging to the following codes of ATC
medical issues, and other characteristics such as age, height, classification: G03C (estrogens), G03F (estrogen and
weight, smoking, alcohol consumption, health disorders diag- progesterone) excluding oral contraceptives. Self-reported use of
nosed by a physician, reproductive history, type and duration estrogen was categorized into postmenopausal HT based on use
of HT use, operations, occupation, and physical activity. These after the onset of menopause.
questionnaires were repeated in the follow-up inquiries.
The present study included those 8,195 women who had Covariates. Baseline menopause status was categorized to 5
complete data on confounders and self-reported exposure. Out- categories: (1) menstruating, no HT; (2) true menopause; (3)
come data and register-based exposure data were available for menstruating, HT 130 years; (4) hysterectomy and HT, no
all participants. oophorectomy; (5) unclear (hysterectomy, no data on oophorec-
tomy or HT use). When categorizing the self-reported HT to
Outcomes. The main outcome of our study was clinically veri- postmenopausal use, a woman was considered postmenopausal if
fied AD diagnosis. These diagnoses from 19992009 were iden- $12 months had passed since her natural menstrual cycle, if she
tified from the Finnish special reimbursement register maintained had undergone surgical menopause through bilateral
by the Social Insurance Institution (SII). The register contains oophorectomy with or without hysterectomy, or if the time
information on the reimbursed drugs used for chronic illnesses since menopause and the history of HT use could be clarified
such as AD. The Finnish special reimbursement register possesses from the follow-up questionnaire. For the present study, we used
high validity and positive predictive value for AD diagnosis.24 The data on natural menopause (i.e., date of last menstruation,
Finnish Current Care Guideline recommends that all persons collected through self-reports at baseline and 5-year follow-up
with AD are treated with antidementia drugs unless there is assessments). Over 90% of women were postmenopausal at the
a specific contraindication (such as gastric ulcer/intestinal tract second follow-up. Missing information was collected from
operation ,6 months ago or severe asthma or chronic obstructive participants by telephone. Body mass index (BMI) was
pulmonary disease for acetylcholinesterase inhibitors).25 In calculated as the ratio of weight in kilograms to height in
Finland, the diagnosis of probable AD is based on DSM-IV meters squared and was based on self-reporting.
criteria for AD and National Institute of Neurologic and Physical activity was inquired through self-reported data in 3
Communicative Disorders and StrokeAlzheimer Disease and ways at baseline and in all follow-up surveys as follows: leisure
Related Disorders Association.26,27 The main diagnostic criteria time physical activity as well as asking about how physically
were progressive decline in memory and cognition and exclusion demanding work was in the last year; ambulatory status as capa-
of other reasons. Diagnosis of AD was supported by abnormal bility and extent of movement, need of aids in movement, and
MRI or CSF biomarker findings typical for AD. history of joint degeneration; and amount of physical activity,
To be eligible for reimbursed AD medication (acetylcholines- including winter and summer activities, amount of current regu-
terase inhibitors or memantine), a medical statement of a clinically lar physical activity, and its duration (hours per week). Of these 3
verified AD diagnosis needs to be submitted to SII. Thus, case categories, the amount of physical activity was the most predictive
identification is carried out in clinics but is reconfirmed by SII. of AD and thus was included in the analyses.
Summary of anamnestic information from the patients and Data on education were obtained in self-reported data only
family, as well as findings, e.g., MRI/CT, laboratory tests, from a subcohort undergoing bone marrow density measure-
and Consortium to Establish a Registry for Alzheimers Disease, ment. Education was categorized into 4 groups: compulsory
are submitted to the SII, where a geriatrician/neurologist schooling, compulsory schooling 1 maximum 2 years of

Neurology 88 March 14, 2017 1063

 supplementary school or occupational training, high school 1 hysterectomy and oophorectomy were strongly correlated (r 5
minimum 2 years of supplementary school or professional 0.561) and were thus combined into one variable (surgery). There
training, and university degree. To assess whether the adjustment were no other indications of collinearity (r , 0.4).
for education affected the results, we conducted a separate sensi- Cox proportional hazard models were used to evaluate the
tivity analyses in the subcohort for whom we had education data association between HT use and AD incidence. Separate analyses
(n 5 2,383). History of ever/never smoking was asked in all self- were carried out for different durations of use and different types
reported questionnaires along with regularity of smoking, num- of HT. Hazard ratios and 95% confidence intervals were esti-
ber of years of smoking, and number of cigarettes smoked per mated with age-adjusted model and model adjusted for age,
day. BMI, alcohol, smoking, physical activity, occupation status,
Data on self-reported occupation were gathered under 9 dif- number of births, menopause status, any cancer, and surgery.
ferent categories (managers; professionals; technicians and associ- Since the education data were available for only a subset of partic-
ate professionals; clerical support workers; service and sales ipants, sensitivity analyses were conducted in this group sepa-
workers; skilled agricultural, fish, and forestry; crafts and related rately. Association between HT and dementia was studied
trades workers; plant and machine operators; other occupation; similarly.
and housewife/pensioner/caregiver/no occupation) but converted We studied whether the association between HT and AD was
into a dichotomous variable (employed and unemployed) for the different among women who had undergone oophorectomy or
analyses. Alcohol consumption was inquired in questionnaires as hysterectomy by assessing the interaction of hysterectomy or
the amount of alcohol beverages consumed during a 1-month oophorectomy and self-reported and register-recorded HT use.
period and converted into grams of alcohol intake per month. There was no evidence for effect modification by these surgeries
At baseline, women were asked in questionnaire about the age (All p values for interaction were .0.6) and thus stratified anal-
at menarche, age at menopause, number of pregnancies, number yses were not performed.
of live births, and abortions. Abortion was inquired in question-
naire as Number of times interrupting pregnancies due to
abortion/miscarriage. A history of any gynecologic operations RESULTS Average age at AD diagnosis was 72.3
(caesarian sections and sterilizations) was also obtained, as well years (range 59.278.6 years). Women who later
as what, if anything, was removed in these operations (uterus, developed AD were significantly older than women
ovary, part of both, cervix, or other parts of genitals). without AD. They also reported less physical activity
Standard protocol approvals, registrations, and patient
and were more likely to be unemployed than
consents. The study design was approved by the Ethics Com- women who were not diagnosed with AD during
mittee of Kuopio University Hospital and written informed con- the follow-up. Number of childbirths, abortions,
sent was obtained from all participants. and pregnancies was similar between groups, but
women who developed AD were more likely to be
Statistical analysis. Statistical analysis was carried out with Sta- menopausal at baseline than those who were not
ta 12.0 (Stata Corp LP, College Station, TX). The characteristics
diagnosed with AD. Register-reported HT or
of women with respect to AD incidence were compared using x2
test for categorical variables and t test for continuous variables. oophorectomy/hysterectomy was not associated
Correlation between confounders and exposure were investigated with AD in these univariable analyses (table e-1 at
with the Spearman correlation coefficient. As expected, Neurology.org).

Table 1 Risk of developing Alzheimer disease (AD) among hormone therapy (HT) users (according to type of
therapy used) in the whole cohort (n 5 8,195)

Incidence
of AD/1,000
HT person-years Model 1 AD Model 2 AD

Any HT use (register-based, since 1995)

No 1.7 1.00 (reference) 1.00 (reference)

Yes 1.4 1.10 (0.851.40) 0.488 1.10 (0.831.40) 0.588

Estrogen use (register-based, since 1995)

No 1.7 1.00 (reference) 1.00 (reference)

Yes 1.4 0.98 (0.741.30) 0.903 0.92 (0.681.20) 0.611

Combination therapy (register-based, since 1995)

No 1.6 1.00 (reference) 1.00 (reference)

Yes 1.4 1.10 (0.851.50) 0.406 1.10 (0.871.50) 0.325

Self-reported estrogen use

No 1.7 1.00 (reference) 1.00 (reference)

Yes 1.5 1.00 (0.821.30) 0.750 0.99 (0.751.30) 0.928

Model 1: adjusted for age. Model 2: adjusted for age, body mass index, alcohol, smoking, physical activity, occupation
status, number of births, menopause status, any cancer, and oophorectomy and hysterectomy.

1064 Neurology 88 March 14, 2017

 Table 2 Risk of developing Alzheimer disease (AD) among hormone therapy (HT) users (register-based) with
different durations of HT use in the whole cohort (n 5 8,195)

Model 1 Model 2
Incidence of AD/1,000
person-years HR (95% CI) p Value HR (95% CI) p Value

Duration of estrogen use, y

None 1.6 1.00 (reference) 1.00 (reference)

<1 1.3 0.89 (0.521.50) 0.670 0.85 (0.491.50) 0.572

13 1.6 1.20 (0.711.90) 0.539 1.10 (0.661.80) 0.728

35 1.6 1.20 (0.652.10) 0.583 1.10 (0.591.90) 0.797

510 1.3 0.88 (0.491.60) 0.675 0.78 (0.421.40) 0.425

>10 0.39 0.29 (0.042.10) 0.221 0.26 (0.031.80) 0.184

Duration of combination therapy use, y

None 1.6 1.00 (reference) 1.00 (reference)

<1 2.2 1.60 (1.102.40) 0.018 1.70 (1.102.60) 0.011

13 1.3 1.00 (0.601.80) 0.889 1.10 (0.621.90) 0.786

35 0.45 0.35 (0.111.10) 0.072 0.36 (0.111.10) 0.080

510 1.6 1.40 (0.862.20) 0.172 1.40 (0.882.30) 0.148

>10 1.7 1.50 (0.653.30) 0.349 1.40 (0.643.30) 0.372

Abbreviations: CI 5 confidence interval; HR 5 hazard ratio.

Model 1: adjusted for age. Model 2: adjusted for age, body mass index, alcohol, smoking, physical activity, occupation
status, number of births, menopause status, any cancer, and surgery.

Table 1 shows the relative risk of AD according to years had lower risk of AD in comparison to nonusers
both register-based and self-reported HT use (yes/ (table 3) also after adjusting for lifestyle and socioeco-
no). Neither register-based nor self-reported HT use nomic confounders and variables related to estrogen
was associated with AD risk. The results were similar status. Sensitivity analyses with any dementia as an
in the sensitivity analyses conducted among those outcome produced similar results to those shown in
with data on education (n 5 2,383; tables e-2 and tables 13, although the association between .10
e-3), i.e., no association was detected between HT use years HT use and AD was attenuated and its confi-
(any HT, estrogen, or combination therapy; either dence also included 1 in the sensitivity analyses (ta-
register-based or self-reported) and AD. bles e-4 to e-6).
HT use when categorized according to duration
register-based HT use was not associated with AD DISCUSSION The findings from our large prospec-
(table 2). However, when self-reported data were tive cohort study do not provide strong evidence for
used, those with longest self-reported HT use .10 an association between postmenopausal HT use and

Table 3 Risk of developing Alzheimer disease (AD) among women using postmenopausal hormone therapy (HT)
(self-reported) in the whole cohort (n 5 8,195)

Model 1 Model 2

Postmenopausal HT, y Incidence of AD/1,000 person-years HR (95% CI) p Value HR (95% CI) p Value

None 1.6 1.00 (reference) 1.00 (reference)

<1 1.8 1.10 (0.691.80) 0.607 1.10 (0.691.80) 0.644

13 1.7 1.10 (0.761.50) 0.670 1.00 (0.721.50) 0.881

35 1.8 1.20 (0.761.80) 0.467 1.10 (0.731.80) 0.558

510 1.3 0.89 (0.611.30) 0.571 0.82 (0.551.20) 0.323

>10 0.97 0.62 (0.381.00) 0.070 0.53 (0.310.91) 0.021

Abbreviations: CI 5 confidence interval; HR 5 hazard ratio.

Model 1: adjusted for age. Model 2: adjusted for age, body mass index, alcohol, smoking, physical activity, occupation
status, number of births, menopause status, any cancer, and surgery.

Neurology 88 March 14, 2017 1065

 AD or dementia, although a protective association One cohort study reported that an early initiation
between long-term (.10 years) self-reported use of of HT around menopause was protective against
HT and AD was observed. This finding indirectly AD.32 Similar findings were reported from the
favors the effectiveness of HT if started in the early Multi-Institutional Research in Alzheimer Genetic
postmenopausal period (critical window theory). Epidemiology study, where HT use in the youngest
Another explanation for this association can be age tertiles (5063 years) protected against AD in
reverse causation, i.e., AD (or more precisely, its comparison to those in the older age tertiles.33
preclinical symptoms) affecting the exposure to HT The lack of association in our cohort between any
(or reporting of HT duration in the self-reported HT use (all users of HT, not taking into account
data), or a chance finding. The association with either the time of initiation or the duration of ther-
longer duration of HT use was only found in self- apy) and AD/dementia is consistent with previous
reported postmenopausal estrogen use, not for observational studies where HT was categorized as
register-based HT use after 1995, and the former or current use and lifetime estrogen exposure
association was less evident when all dementia was taken into account.34,35 Postmenopausal estrogen
diagnoses instead of clinically verified AD diagnosis therapy was not protective against AD in 2 of the
were used as an outcome. One explanation for the case-control studies.18,20 This discrepancy in observa-
different results with self-reported and register-based tional studies is explained by differences in outcome
exposure could be different time period as register measurement, number of observations, duration,
data were not available before 1995, which is 7 type, and the time of initiation of HT use.
years after the baseline inquiry. Thus, the register- The strengths of our study include its large sample
based data after 1995 would misclassify those who size, long follow-up time, relatively homogenous pop-
discontinued HT use before 1995 as nonusers. It is ulation, clinically verified AD cases, prescription-
unlikely that this misclassification was differential in based validation of HT use, and control for various
those who later developed AD and those who did not. important comorbidities. Confounders and exposures
Therefore it would lead to an underestimation of the were measured with the same questions during the
association between HT use and AD with the follow-up. In addition, the positive predictive value
register-based data after 1995. An alternative of AD diagnosis in the Special Reimbursement Regis-
explanation is recall bias, but this is unlikely as ter is high.24 However, it is likely that this register
previous validation study from the same cohort does not capture all AD cases, or persons with other
showed that a postal inquiry is a reliable method forms of dementia. Therefore we conducted sensitiv-
of recording long-term HT use in Finnish ity analysis with any dementia as an outcome. Despite
postmenopausal women.28 these strengths, our study has some limitations: first,
Our result is in line with the extended follow-up information was collected by self-reported postal
of the Cache County Study, which detected a reduced inquiries, which may be subject to recall bias; second,
AD risk if HT was started within 5 years of meno- the effect of healthy user bias among the long-term
pause and continued for more than 10 years.15 The users cannot be overlooked; third, register data on
largest clinical trial on HTall cause dementia associ- HT use and AD diagnosis were available from 1995
ation, i.e., WHIMS, assessed cognitive performance to 1999 onwards, respectively; fourth, we cannot
of women .65 years old, assigned to conjugated eliminate the chance of a survival bias contributing
equine estrogen (CEE; unopposed therapy) vs pla- to the protective association observed among the lon-
cebo or continuous CEE 1 medroxyprogesterone gest HT users; fifth, we were not able to control the
acetate (CEE 1 MPA; opposed therapy) vs placebo. results for genetic predisposition to AD (APOE status
The use of opposed HT increased the dementia risk, and familial AD). However, it is unlikely that these
but this did not occur with unopposed HT.14,29 In the genetic factors would influence start of HT use and
WHIMS trial, women were randomized to receive thus it is unlikely that the results are confounded by
opposed therapy as CEE combined with MPA. In genetic background.
Finland, estradiol in combination with norethisterone Misclassification of outcome (i.e., undiagnosed
or levonorgestrel (not MPA) is used among women AD or dementia cases) is possible and this would
with intact uterus30 and only estradiol is used mainly dilute our estimates towards the null. However, the
among women undergoing hysterectomy.31 The dif- proportion of misclassified persons is likely to be
ference between these 2 studies may be attributable to small. Due to our outcome data source in sensitivity
the differences in the effects exerted by the different analyses for dementia, we captured only those persons
estrogen preparations. In addition, the women in our with dementia who required inpatient admission (due
cohort were around 10 years younger than women in to dementia or other disease/accident). The diagnos-
the WHI trial, and the main outcome in our study tic process for dementia often begins in an outpatient
was AD, while it was all-cause dementia in WHIMS. setting, but these settings were not included in the

1066 Neurology 88 March 14, 2017

hospital discharge register. Therefore, those persons 2. Hebert LE, Scherr PA, McCann JJ, Beckett LA, Evans DA.
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3. Seshadri S, Wolf PA, Beiser A, et al. Lifetime risk of
Our study examined a homogenous population
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a defined elderly Japanese population: the Hisayama
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Our results based on 2 decades of follow-up of The estrogen replacement therapy of the Womens Health
Initiative promotes the cellular mechanisms of memory
a large homogenous population did not provide
and neuronal survival in neurons vulnerable to Alzheimers
strong evidence for a protective association between
disease. Maturitas 2000;34(suppl 2):S35S52.
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AUTHOR CONTRIBUTIONS 9. Tanapat P, Hastings NB, Reeves AJ, Gould E. Estrogen
Dr. Imtiaz: planned the research project, drafted the first version of the stimulates a transient increase in the number of new neu-
manuscript, performed statistical analyses, acts as guarantor, accepted
rons in the dentate gyrus of the adult female rat.
the submitted version of the manuscript, and made important intellectual
J Neurosci 1999;19:57925801.
contribution to draft versions. Dr. Tuppurainen: planned the research
project, participated in data collection, accepted the submitted version
10. Behl C. Oestrogen as a neuroprotective hormone. Nat Rev
of the manuscript, and made important intellectual contribution to draft Neurosci 2002;3:433442.
versions. Dr. Rikkonen: participated in data analysis, accepted the sub- 11. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen
mitted version of the manuscript, and made important intellectual contri- for Alzheimers disease in women: randomized, double-blind,
bution to draft versions. Prof. Kivipelto: accepted the submitted version placebo-controlled trial. Neurology 2000;54:295301.
of the manuscript and made important intellectual contribution to draft 12. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen
versions. Prof. Soininen: planned the research project, accepted the sub- replacement therapy for treatment of mild to moderate
mitted version of the manuscript, and made important intellectual contri-
Alzheimer disease: a randomized controlled trial: Alz-
bution to draft versions. Prof. Krger: planned the research project,
heimers Disease Cooperative Study. JAMA 2000;283:
participated in data collection, accepted the submitted version of the
manuscript, and made important intellectual contribution to draft ver- 10071015.
sions. Dr. Tolppanen: planned the research project, supervised data anal- 13. Wang PN, Liao SQ, Liu RS, et al. Effects of estrogen on
yses and the research project, accepted the submitted version of the cognition, mood, and cerebral blood flow in AD: a con-
manuscript, and made important intellectual contribution to draft trolled study. Neurology 2000;54:20612066.
versions. 14. Shumaker SA, Legault C, Rapp SR, et al; WHIMS Inves-
tigators. Estrogen plus progestin and the incidence of
ACKNOWLEDGMENT dementia and mild cognitive impairment in postmeno-
The authors thank Seija Oinonen for technical help regarding data pausal women: the Womens Health Initiative Memory
extraction. Study: a randomized controlled trial. JAMA 2003;289:
26512662.
STUDY FUNDING 15. Shao H, Breitner JC, Whitmer RA, et al; Cache County
Supported by Kuopio Osteoporosis Risk Factor and Prevention Investigators. Hormone therapy and Alzheimer disease
(OSTPRE) grant 250707. A.M.T. acknowledges funding from European dementia: new findings from the Cache County Study.
Regional Development Fund (regional council of Pohjois Savo), M.K. is
Neurology 2012;79:18461852.
a recipient of Academy of Finland and Center for Innovative Medicine
16. Whitmer RA, Quesenberry CP, Zhou J, Yaffe K. Timing
(CIMED), and H.S. received funding from the University of Eastern
Finland for UEF Brain. B.I. acknowledges The Finnish Cultural Foundation
of hormone therapy and dementia: the critical window
(central fund) and funding by Doctoral Program of Molecular Medicine, theory revisited. Ann Neurol 2011;69:163169.
University of Eastern Finland. 17. Barnes LL, Wilson RS, Schneider JA, Bienias JL, Evans
DA, Bennett DA. Gender, cognitive decline, and risk of
DISCLOSURE AD in older persons. Neurology 2003;60:17771781.
The authors report no disclosures relevant to the manuscript. Go to 18. Brenner DE, Kukull WA, Stergachis A, et al. Postmeno-
Neurology.org for full disclosures. pausal estrogen replacement therapy and the risk of Alz-
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Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study
Bushra Imtiaz, Marjo Tuppurainen, Toni Rikkonen, et al.
Neurology 2017;88;1062-1068 Published Online before print February 15, 2017
DOI 10.1212/WNL.0000000000003696

This information is current as of February 15, 2017

Updated Information & including high resolution figures, can be found at:
Services http://www.neurology.org/content/88/11/1062.full.html

Supplementary Material Supplementary material can be found at:

http://www.neurology.org/content/suppl/2017/02/15/WNL.0000000000
003696.DC1
References This article cites 35 articles, 17 of which you can access for free at:
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