the present study is based on the 20-year follow - up of the population of the kuopio osteoporosis risk factor and prevention study cohort .
a self - administered baseline postal questionnaire was sent to all women aged 4756 years who were residents of kuopio province , eastern finland ( n = 14,220 ) , in february 1989 .
the reasons for nonresponse were lack of address or residence not detected ( n = 119 ) and death ( n = 4 ) .
in addition , 947 women did not respond for other reasons and 50 returned a blank form . the 5-year follow - up in 1994 , 10-year follow - up in 1999 , 15-year follow - up in 2004 , and 20-year follow - up in 2009
was mailed to the 13,100 , 12,562 , 12,075 , and 11,420 women , respectively .
a total of 11,954 ( 91.2% ) , 11,538 ( 91.8% ) , 10,926 ( 90.4% ) , and 8,195 ( 71.8% ) women responded to the 5- , 10- , 15- , and 20-year follow - ups , respectively .
the questionnaires were sent to women who had responded to the baseline inquiry , were alive , and had a valid postal address at that time . the baseline questionnaire covered demographics , lifestyle , medical issues , and other characteristics such as age , height , weight , smoking , alcohol consumption , health disorders diagnosed by a physician , reproductive history , type and duration of ht use , operations , occupation , and physical activity .
the present study included those 8,195 women who had complete data on confounders and self - reported exposure .
these diagnoses from 19992009 were identified from the finnish special reimbursement register maintained by the social insurance institution ( sii ) .
the register contains information on the reimbursed drugs used for chronic illnesses such as ad .
the finnish special reimbursement register possesses high validity and positive predictive value for ad diagnosis .
the finnish current care guideline recommends that all persons with ad are treated with antidementia drugs unless there is a specific contraindication ( such as gastric ulcer / intestinal tract operation < 6 months ago or severe asthma or chronic obstructive pulmonary disease for acetylcholinesterase inhibitors ) . in finland
, the diagnosis of probable ad is based on dsm - iv criteria for ad and national institute of neurologic and communicative disorders and stroke 
the main diagnostic criteria were progressive decline in memory and cognition and exclusion of other reasons .
diagnosis of ad was supported by abnormal mri or csf biomarker findings typical for ad . to be eligible for reimbursed ad medication ( acetylcholinesterase inhibitors or memantine ) , a medical statement of a clinically verified ad diagnosis
summary of anamnestic information from the patients and family , as well as findings , e.g. , mri / ct , laboratory tests , and consortium to establish a registry for alzheimer 's disease , are submitted to the sii , where a geriatrician / neurologist systematically evaluates the diagnostic evidence for each ad case and confirms whether the prespecified criteria are met excluding possible alternative diagnoses for memory impairment such as severe depression , metabolic disturbances , and other forms of dementia such as vascular dementia without ad - like symptoms .
these data were extracted from the national hospital discharge register using the following icd-10 codes : f00f03 ( f00 , dementia in alzheimer disease ; f01 , vascular dementia ; f02 , dementia in other diseases classified elsewhere ; f03 , unspecified dementia ) and g30 ( alzheimer disease , early / late onset ) .
all finnish citizens / long - term residents are covered by tax - supported public health service .
self - reported ht use was recorded as lifetime use in years ( and indication of use ) at the baseline inquiry in 1989 . in all
follow - up questionnaires , numbers of months per year of estrogen use were reported and the duration of self - reported estrogen use was calculated on basis of these questionnaires .
current medication prescribed by a physician , duration and purpose of use , and name of tablets used were asked in all inquiries . to exclude the possibility of recall bias in the self - reported questionnaires
ht was defined from the registry as those preparations having systemic estrogenic properties belonging to the following codes of atc classification : g03c ( estrogens ) , g03f ( estrogen and progesterone ) excluding oral contraceptives .
self - reported use of estrogen was categorized into postmenopausal ht based on use after the onset of menopause .
baseline menopause status was categorized to 5 categories : ( 1 ) menstruating , no ht ; ( 2 ) true menopause ; ( 3 ) menstruating , ht 130 years ; ( 4 ) hysterectomy and ht , no oophorectomy ; ( 5 ) unclear ( hysterectomy , no data on oophorectomy or ht use ) .
when categorizing the self - reported ht to postmenopausal use , a woman was considered postmenopausal if 12 months had passed since her natural menstrual cycle , if she had undergone surgical menopause through bilateral oophorectomy with or without hysterectomy , or if the time since menopause and the history of ht use could be clarified from the follow - up questionnaire . for the present study
, we used data on natural menopause ( i.e. , date of last menstruation , collected through self - reports at baseline and 5-year follow - up assessments ) . over 90% of women were postmenopausal at the second follow - up . missing information
body mass index ( bmi ) was calculated as the ratio of weight in kilograms to height in meters squared and was based on self - reporting .
physical activity was inquired through self - reported data in 3 ways at baseline and in all follow - up surveys as follows : leisure time physical activity as well as asking about how physically demanding work was in the last year ; ambulatory status as capability and extent of movement , need of aids in movement , and history of joint degeneration ; and amount of physical activity , including winter and summer activities , amount of current regular physical activity , and its duration ( hours per week ) . of these 3 categories ,
the amount of physical activity was the most predictive of ad and thus was included in the analyses .
data on education were obtained in self - reported data only from a subcohort undergoing bone marrow density measurement .
education was categorized into 4 groups : compulsory schooling , compulsory schooling + maximum 2 years of supplementary school or occupational training , high school + minimum 2 years of supplementary school or professional training , and university degree . to assess
whether the adjustment for education affected the results , we conducted a separate sensitivity analyses in the subcohort for whom we had education data ( n = 2,383 ) .
history of ever / never smoking was asked in all self - reported questionnaires along with regularity of smoking , number of years of smoking , and number of cigarettes smoked per day .
data on self - reported occupation were gathered under 9 different categories ( managers ; professionals ; technicians and associate professionals ; clerical support workers ; service and sales workers ; skilled agricultural , fish , and forestry ; crafts and related trades workers ; plant and machine operators ; other occupation ; and housewife / pensioner / caregiver / no occupation ) but converted into a dichotomous variable ( employed and unemployed ) for the analyses .
alcohol consumption was inquired in questionnaires as the amount of alcohol beverages consumed during a 1-month period and converted into grams of alcohol intake per month . at baseline
, women were asked in questionnaire about the age at menarche , age at menopause , number of pregnancies , number of live births , and abortions .
abortion was inquired in questionnaire as  number of times interrupting pregnancies due to abortion / miscarriage .  a history of any gynecologic operations ( caesarian sections and sterilizations ) was also obtained , as well as what , if anything , was removed in these operations ( uterus , ovary , part of both , cervix , or other parts of genitals ) .
the study design was approved by the ethics committee of kuopio university hospital and written informed consent was obtained from all participants .
statistical analysis was carried out with stata 12.0 ( stata corp lp , college station , tx ) .
the characteristics of women with respect to ad incidence were compared using  test for categorical variables and t test for continuous variables .
as expected , hysterectomy and oophorectomy were strongly correlated ( r = 0.561 ) and were thus combined into one variable ( surgery ) .
cox proportional hazard models were used to evaluate the association between ht use and ad incidence .
separate analyses were carried out for different durations of use and different types of ht .
hazard ratios and 95% confidence intervals were estimated with age - adjusted model and model adjusted for age , bmi , alcohol , smoking , physical activity , occupation status , number of births , menopause status , any cancer , and surgery .
since the education data were available for only a subset of participants , sensitivity analyses were conducted in this group separately .
we studied whether the association between ht and ad was different among women who had undergone oophorectomy or hysterectomy by assessing the interaction of hysterectomy or oophorectomy and self - reported and register - recorded ht use .
there was no evidence for effect modification by these surgeries ( all p values for interaction were > 0.6 ) and thus stratified analyses were not performed .
the present study is based on the 20-year follow - up of the population of the kuopio osteoporosis risk factor and prevention study cohort .
a self - administered baseline postal questionnaire was sent to all women aged 4756 years who were residents of kuopio province , eastern finland ( n = 14,220 ) , in february 1989 .
the reasons for nonresponse were lack of address or residence not detected ( n = 119 ) and death ( n = 4 ) .
in addition , 947 women did not respond for other reasons and 50 returned a blank form . the 5-year follow - up in 1994 , 10-year follow - up in 1999 , 15-year follow - up in 2004 , and 20-year follow - up in 2009
was mailed to the 13,100 , 12,562 , 12,075 , and 11,420 women , respectively .
a total of 11,954 ( 91.2% ) , 11,538 ( 91.8% ) , 10,926 ( 90.4% ) , and 8,195 ( 71.8% ) women responded to the 5- , 10- , 15- , and 20-year follow - ups , respectively .
the questionnaires were sent to women who had responded to the baseline inquiry , were alive , and had a valid postal address at that time . the baseline questionnaire covered demographics , lifestyle , medical issues , and other characteristics such as age , height , weight , smoking , alcohol consumption , health disorders diagnosed by a physician , reproductive history , type and duration of ht use , operations , occupation , and physical activity .
the present study included those 8,195 women who had complete data on confounders and self - reported exposure .
the main outcome of our study was clinically verified ad diagnosis . these diagnoses from 19992009 were identified from the finnish special reimbursement register maintained by the social insurance institution ( sii ) .
the register contains information on the reimbursed drugs used for chronic illnesses such as ad .
the finnish special reimbursement register possesses high validity and positive predictive value for ad diagnosis .
the finnish current care guideline recommends that all persons with ad are treated with antidementia drugs unless there is a specific contraindication ( such as gastric ulcer / intestinal tract operation < 6 months ago or severe asthma or chronic obstructive pulmonary disease for acetylcholinesterase inhibitors ) . in finland ,
the diagnosis of probable ad is based on dsm - iv criteria for ad and national institute of neurologic and communicative disorders and stroke 
the main diagnostic criteria were progressive decline in memory and cognition and exclusion of other reasons .
diagnosis of ad was supported by abnormal mri or csf biomarker findings typical for ad . to be eligible for reimbursed ad medication ( acetylcholinesterase inhibitors or memantine ) , a medical statement of a clinically verified ad diagnosis
summary of anamnestic information from the patients and family , as well as findings , e.g. , mri / ct , laboratory tests , and consortium to establish a registry for alzheimer 's disease , are submitted to the sii , where a geriatrician / neurologist systematically evaluates the diagnostic evidence for each ad case and confirms whether the prespecified criteria are met excluding possible alternative diagnoses for memory impairment such as severe depression , metabolic disturbances , and other forms of dementia such as vascular dementia without ad - like symptoms .
these data were extracted from the national hospital discharge register using the following icd-10 codes : f00f03 ( f00 , dementia in alzheimer disease ; f01 , vascular dementia ; f02 , dementia in other diseases classified elsewhere ; f03 , unspecified dementia ) and g30 ( alzheimer disease , early / late onset ) .
all finnish citizens / long - term residents are covered by tax - supported public health service .
self - reported ht use was recorded as lifetime use in years ( and indication of use ) at the baseline inquiry in 1989 . in all
follow - up questionnaires , numbers of months per year of estrogen use were reported and the duration of self - reported estrogen use was calculated on basis of these questionnaires .
current medication prescribed by a physician , duration and purpose of use , and name of tablets used were asked in all inquiries . to exclude the possibility of recall bias in the self - reported questionnaires
ht was defined from the registry as those preparations having systemic estrogenic properties belonging to the following codes of atc classification : g03c ( estrogens ) , g03f ( estrogen and progesterone ) excluding oral contraceptives .
self - reported use of estrogen was categorized into postmenopausal ht based on use after the onset of menopause .
baseline menopause status was categorized to 5 categories : ( 1 ) menstruating , no ht ; ( 2 ) true menopause ; ( 3 ) menstruating , ht 130 years ; ( 4 ) hysterectomy and ht , no oophorectomy ; ( 5 ) unclear ( hysterectomy , no data on oophorectomy or ht use ) .
when categorizing the self - reported ht to postmenopausal use , a woman was considered postmenopausal if 12 months had passed since her natural menstrual cycle , if she had undergone surgical menopause through bilateral oophorectomy with or without hysterectomy , or if the time since menopause and the history of ht use could be clarified from the follow - up questionnaire . for the present study , we used data on natural menopause ( i.e. , date of last menstruation , collected through self - reports at baseline and 5-year follow - up assessments ) . over 90% of women were postmenopausal at the second follow - up . missing information
body mass index ( bmi ) was calculated as the ratio of weight in kilograms to height in meters squared and was based on self - reporting .
physical activity was inquired through self - reported data in 3 ways at baseline and in all follow - up surveys as follows : leisure time physical activity as well as asking about how physically demanding work was in the last year ; ambulatory status as capability and extent of movement , need of aids in movement , and history of joint degeneration ; and amount of physical activity , including winter and summer activities , amount of current regular physical activity , and its duration ( hours per week ) . of these 3 categories ,
the amount of physical activity was the most predictive of ad and thus was included in the analyses .
data on education were obtained in self - reported data only from a subcohort undergoing bone marrow density measurement .
education was categorized into 4 groups : compulsory schooling , compulsory schooling + maximum 2 years of supplementary school or occupational training , high school + minimum 2 years of supplementary school or professional training , and university degree . to assess
whether the adjustment for education affected the results , we conducted a separate sensitivity analyses in the subcohort for whom we had education data ( n = 2,383 ) .
history of ever / never smoking was asked in all self - reported questionnaires along with regularity of smoking , number of years of smoking , and number of cigarettes smoked per day .
data on self - reported occupation were gathered under 9 different categories ( managers ; professionals ; technicians and associate professionals ; clerical support workers ; service and sales workers ; skilled agricultural , fish , and forestry ; crafts and related trades workers ; plant and machine operators ; other occupation ; and housewife / pensioner / caregiver / no occupation ) but converted into a dichotomous variable ( employed and unemployed ) for the analyses .
alcohol consumption was inquired in questionnaires as the amount of alcohol beverages consumed during a 1-month period and converted into grams of alcohol intake per month . at baseline
, women were asked in questionnaire about the age at menarche , age at menopause , number of pregnancies , number of live births , and abortions .
abortion was inquired in questionnaire as  number of times interrupting pregnancies due to abortion / miscarriage .
 a history of any gynecologic operations ( caesarian sections and sterilizations ) was also obtained , as well as what , if anything , was removed in these operations ( uterus , ovary , part of both , cervix , or other parts of genitals ) .
the study design was approved by the ethics committee of kuopio university hospital and written informed consent was obtained from all participants .
statistical analysis was carried out with stata 12.0 ( stata corp lp , college station , tx ) .
the characteristics of women with respect to ad incidence were compared using  test for categorical variables and t test for continuous variables .
as expected , hysterectomy and oophorectomy were strongly correlated ( r = 0.561 ) and were thus combined into one variable ( surgery ) .
cox proportional hazard models were used to evaluate the association between ht use and ad incidence .
separate analyses were carried out for different durations of use and different types of ht .
hazard ratios and 95% confidence intervals were estimated with age - adjusted model and model adjusted for age , bmi , alcohol , smoking , physical activity , occupation status , number of births , menopause status , any cancer , and surgery .
since the education data were available for only a subset of participants , sensitivity analyses were conducted in this group separately .
we studied whether the association between ht and ad was different among women who had undergone oophorectomy or hysterectomy by assessing the interaction of hysterectomy or oophorectomy and self - reported and register - recorded ht use .
there was no evidence for effect modification by these surgeries ( all p values for interaction were > 0.6 ) and thus stratified analyses were not performed .
they also reported less physical activity and were more likely to be unemployed than women who were not diagnosed with ad during the follow - up .
number of childbirths , abortions , and pregnancies was similar between groups , but women who developed ad were more likely to be menopausal at baseline than those who were not diagnosed with ad .
register - reported ht or oophorectomy / hysterectomy was not associated with ad in these univariable analyses ( table e-1 at neurology.org ) .
table 1 shows the relative risk of ad according to both register - based and self - reported ht use ( yes / no ) .
neither register - based nor self - reported ht use was associated with ad risk .
the results were similar in the sensitivity analyses conducted among those with data on education ( n = 2,383 ; tables e-2 and e-3 ) , i.e. , no association was detected between ht use ( any ht , estrogen , or combination therapy ; either register - based or self - reported ) and ad .
risk of developing alzheimer disease ( ad ) among hormone therapy ( ht ) users ( according to type of therapy used ) in the whole cohort ( n = 8,195 ) ht use when categorized according to duration register - based ht use was not associated with ad ( table 2 ) . however ,
when self - reported data were used , those with longest self - reported ht use > 10 years had lower risk of ad in comparison to nonusers ( table 3 ) also after adjusting for lifestyle and socioeconomic confounders and variables related to estrogen status .
sensitivity analyses with any dementia as an outcome produced similar results to those shown in tables 13 , although the association between > 10 years ht use and ad was attenuated and its confidence also included 1 in the sensitivity analyses ( tables e-4 to e-6 ) .
risk of developing alzheimer disease ( ad ) among hormone therapy ( ht ) users ( register - based ) with different durations of ht use in the whole cohort ( n = 8,195 ) risk of developing alzheimer disease ( ad ) among women using postmenopausal hormone therapy ( ht ) ( self - reported ) in the whole cohort ( n = 8,195 )
the findings from our large prospective cohort study do not provide strong evidence for an association between postmenopausal ht use and ad or dementia , although a protective association between long - term ( > 10 years ) self - reported use of ht and ad was observed .
this finding indirectly favors the effectiveness of ht if started in the early postmenopausal period ( critical window theory ) .
another explanation for this association can be reverse causation , i.e. , ad ( or more precisely , its preclinical symptoms ) affecting the exposure to ht ( or reporting of ht duration in the self - reported data ) , or a chance finding .
the association with longer duration of ht use was only found in self - reported postmenopausal estrogen use , not for register - based ht use after 1995 , and the association was less evident when all dementia diagnoses instead of clinically verified ad diagnosis were used as an outcome .
one explanation for the different results with self - reported and register - based exposure could be different time period as register data were not available before 1995 , which is 7 years after the baseline inquiry .
thus , the register - based data after 1995 would misclassify those who discontinued ht use before 1995 as nonusers .
it is unlikely that this misclassification was differential in those who later developed ad and those who did not
. therefore it would lead to an underestimation of the association between ht use and ad with the register - based data after 1995 .
an alternative explanation is recall bias , but this is unlikely as previous validation study from the same cohort showed that a postal inquiry is a reliable method of recording long - term ht use in finnish postmenopausal women .
our result is in line with the extended follow - up of the cache county study , which detected a reduced ad risk if ht was started within 5 years of menopause and continued for more than 10 years .
the largest clinical trial on ht  all cause dementia association , i.e. , whims , assessed cognitive performance of women > 65 years old , assigned to conjugated equine estrogen ( cee ; unopposed therapy ) vs placebo or continuous cee + medroxyprogesterone acetate ( cee + mpa ; opposed therapy ) vs placebo .
the use of opposed ht increased the dementia risk , but this did not occur with unopposed ht . in the whims trial , women were randomized to receive opposed therapy as cee combined with mpa . in finland , estradiol in combination with norethisterone or levonorgestrel ( not mpa ) is used among women with intact uterus and only estradiol is used mainly among women undergoing hysterectomy .
the difference between these 2 studies may be attributable to the differences in the effects exerted by the different estrogen preparations .
in addition , the women in our cohort were around 10 years younger than women in the whi trial , and the main outcome in our study was ad , while it was all - cause dementia in whims .
one cohort study reported that an early initiation of ht around menopause was protective against ad .
similar findings were reported from the multi - institutional research in alzheimer genetic epidemiology study , where ht use in the youngest age tertiles ( 5063 years ) protected against ad in comparison to those in the older age tertiles .
the lack of association in our cohort between any ht use ( all users of ht , not taking into account either the time of initiation or the duration of therapy ) and ad / dementia is consistent with previous observational studies where ht was categorized as former or current use and lifetime estrogen exposure was taken into account .
postmenopausal estrogen therapy was not protective against ad in 2 of the case - control studies .
this discrepancy in observational studies is explained by differences in outcome measurement , number of observations , duration , type , and the time of initiation of ht use .
the strengths of our study include its large sample size , long follow - up time , relatively homogenous population , clinically verified ad cases , prescription - based validation of ht use , and control for various important comorbidities .
in addition , the positive predictive value of ad diagnosis in the special reimbursement register is high .
however , it is likely that this register does not capture all ad cases , or persons with other forms of dementia
. therefore we conducted sensitivity analysis with any dementia as an outcome . despite these strengths ,
our study has some limitations : first , information was collected by self - reported postal inquiries , which may be subject to recall bias ; second , the effect of healthy user bias among the long - term users can not be overlooked ; third , register data on ht use and ad diagnosis were available from 1995 to 1999 onwards , respectively ; fourth , we can not eliminate the chance of a survival bias contributing to the protective association observed among the longest ht users ; fifth , we were not able to control the results for genetic predisposition to ad ( apoe status and familial ad ) .
however , it is unlikely that these genetic factors would influence start of ht use and thus it is unlikely that the results are confounded by genetic background .
misclassification of outcome ( i.e. , undiagnosed ad or dementia cases ) is possible and this would dilute our estimates towards the null . however , the proportion of misclassified persons is likely to be small . due to our outcome data source in sensitivity analyses for dementia
, we captured only those persons with dementia who required inpatient admission ( due to dementia or other disease / accident ) .
the diagnostic process for dementia often begins in an outpatient setting , but these settings were not included in the hospital discharge register .
therefore , those persons with dementia who did not have any hospital admissions or antidementia medications were misclassified .
our study examined a homogenous population ( residents of kuopio province , all accessed via the national social security system ) , thus decreasing the chances of selection bias or confounding by socioeconomic - related factors .
some previous observational studies carried out in sociodemographic homogenous populations have observed decreased risk of ad among ht users .
estrogen replacement therapy was protective against ad in these studies and sociodemographic heterogeneity may account for the contrasting results obtained in the 2 observational studies .
our results based on 2 decades of follow - up of a large homogenous population did not provide strong evidence for a protective association between postmenopausal ht use and ad or dementia .
dr . imtiaz : planned the research project , drafted the first version of the manuscript , performed statistical analyses , acts as guarantor , accepted the submitted version of the manuscript , and made important intellectual contribution to draft versions .
tuppurainen : planned the research project , participated in data collection , accepted the submitted version of the manuscript , and made important intellectual contribution to draft versions .
rikkonen : participated in data analysis , accepted the submitted version of the manuscript , and made important intellectual contribution to draft versions .
kivipelto : accepted the submitted version of the manuscript and made important intellectual contribution to draft versions .
soininen : planned the research project , accepted the submitted version of the manuscript , and made important intellectual contribution to draft versions .
krger : planned the research project , participated in data collection , accepted the submitted version of the manuscript , and made important intellectual contribution to draft versions .
tolppanen : planned the research project , supervised data analyses and the research project , accepted the submitted version of the manuscript , and made important intellectual contribution to draft versions .
a.m.t . acknowledges funding from european regional development fund ( regional council of pohjois savo ) , m.k .
is a recipient of academy of finland and center for innovative medicine ( cimed ) , and h.s .
acknowledges the finnish cultural foundation ( central fund ) and funding by doctoral program of molecular medicine , university of eastern finland .
 objective : to explore the association between postmenopausal hormone therapy ( ht ) and alzheimer disease ( ad).methods : twenty - year follow - up data from the kuopio osteoporosis risk factor and prevention study cohort were used . 
 self - administered questionnaires were sent to all women aged 4756 years , residing in kuopio province starting in 1989 until 2009 , every 5th year . 
 register - based information on ht prescriptions was available since 1995 . 
 probable ad cases , based on dsm - iv and national institute of neurological and communicative disorders and stroke  
 alzheimer 's disease and related disorders association criteria , were identified from the special reimbursement register ( 19992009 ) . 
 the study population included 8,195 women ( 227 cases of incident ad).results : postmenopausal estrogen use was not associated with ad risk in register - based or self - reported data ( hazard ratio/95% confidence interval 0.92/0.681.2 , 0.99/0.751.3 , respectively ) . 
 long - term self - reported postmenopausal ht was associated with reduced ad risk ( 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 . 
METHODS
Study population.
Outcomes.
Use of HT.
Covariates.
Standard protocol approvals, registrations, and patient consents.
Statistical analysis.
RESULTS
DISCUSSION
Supplementary Material
AUTHOR CONTRIBUTIONS
STUDY FUNDING
DISCLOSURE