This is an observational cohort study of long-term female members of the Kaiser Permanente Medical Care Program of Northern California who participated in periodic multiphasic health checkups (MHC) that were part of routine medical care, in San Francisco and Oakland, CA, between 1964 and 1973 when they were 40–55 years old (N=7758). Kaiser Permanente of Northern California is a nonprofit, group-practice health integrated delivery system that covers more than one fourth of the population in the geographic areas served. Kaiser Permanente members are representative of the sociodemographics of the local population 16
. Our analytic sample only included women who self-reported as being post-menopausal at time of the MHC exam, who were also alive and health plan membersin 1994; and without a diagnosis of dementia prior to 1999 (N=5504).
Mid-life Data collection
At the MHC, participants were interviewed and information on demographics, lifestyle, and medical history was collected including questions on medical conditions, menopausal status, and medication use 17
. Women were asked if they were currently taking hormones. Women were considered to be taking mid-life HT if they answered yes to the question, and were not on thyroid hormones and did not have a self report of endocrine diseases. Women were also asked about menopausal status, number of children, history of miscarriages, and hysterectomy status. Systolic and diastolic blood pressure, weight, and height were measured according to standard procedures17
and body mass index was calculated (kg/m2
). Blood was drawn for total serum cholesterol and fasting glucose. The participants were considered to have mid-life hypertension if they had one of the following: self-report of physician diagnosed hypertension, use of antihypertensive medication, systolic blood pressure ≥140 mm Hg, or diastolic blood pressure ≥90 mm Hg. Mid-life diabetes was defined by self report of physician diagnosed diabetes, use of insulin or oral hypoglycemic agents, a fasting glucose (last food eaten in ≥8 hours) of ≥140 mg/dl, or a non-fasting (last food eaten in ≤4 hours) glucose of ≥200 mg/dl. Oophorectomy status from 1971–1974 was collected from hospitalization database using ICD-9 procedure codes : 65.3x, 65.4x, 65.5x, and 65.6x. From 1971 until the end of the study hysterectomy procedures were collected from our hospitalization database using ICD-9 procedure codes (68.0. 68.1, 68.2, 68.3, 68.4, 68.5, 68.6, 68.7, 68.8, 68.9).
Late- Life hormone therapy
From January 1,1994-December 31, 1998 KPNC pharmacy databases were searched for prescriptions of HT. The KPNC pharmacy database was implemented in all facilities in 1994, and contains prescription medications dispensed at KP hospitals, medical centers and medical offices. The pharmacy data contains medical record number, medicine name, date of prescription, dosage and refill information. All types of oral and patch HT were included, (estrogen only and estrogen/progesterone combinations). Vaginal creams were not included given the lack of data to suggest a systemic effect on the central nervous system. Those with two or more prescriptions or refills of HT during the four years were considered as late-life HT users. Each prescription is a 100 day prescription, thus the criteria of two or more prescriptions is equal to approximately six months of HT use.
Dementia diagnoses were ascertained through electronic medical records from a database that contains diagnoses from all outpatient and inpatient encounters at Kaiser Permanente medical centers and clinics. The form is completed by the treating clinician. Diagnoses considered in this study included AD (ICD 9 CM code 331.0) and VaD (ICD 9 CM code 290.4) from visits to Neurology and Neuropsychology and diagnoses of dementia (ICD 9 CM 290.0) from visits to Internal Medicine. Participants were considered to have dementia if they had any one of the diagnoses. Diagnoses were ascertained from January 1, 1999 to June 2008 when the MHC participants were between 75 and 84 at the commencement of dementia ascertainment, and between 84 and 93 years of age at the completion of the ascertainment. Those with diagnoses of dementia, cognitive impairment or general memory complaints prior to commencement of dementia ascertainment in January 1, 1999 were excluded from the study (N=343).
Latelife Comorbidities and Mortality
Stroke was recorded from hospital discharge diagnoses (ICD-9 codes for ischemic stroke, 433–438, hemorrhagic stroke, 430–432) from 1971 through the end of the study, June 2008. Late-life diabetes status was ascertained from our diabetes registry,18–20
a continuously maintained registry of KP patients with type 1 and type 2 diabetes, that is 99% specific, from 1994 though 2008. Hypertension (ICD-9 codes 401.x-405.x) and hyperlipidemia (ICD-9 codes 272.0, 272.1, 272.2) were recorded from our outpatient databases from 1994–2008. Mortality information was available on our cohort through the end of 2007.
All analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC). Mid-life and late-life HT information was combined to examine 4 possible groups of women: those not on HT in mid or late-life (never), those on HT both in mid and late-life (both), those on HT only in mid-life (mid-life), those on HT only in late-life (late-life). Preliminary analyses included chi-square χ2 tests and t tests used to determine if demographic and clinical characteristics were significantly different by HT group (four groups). Since the majority of dementia cases occurred in women over age 80, we examined frequency of dementia cases stratified by median age in 1999 (80.4 years), across the four HT groups (never, mid-life, late-life and both). Unadjusted age as time scale Kaplan Meier survival curves of dementia risk were conducted to examine the likelihood of dementia over age and time by the four HT groups. We then used Cox proportional hazard regression models with age as time scale to investigate the independent relationship between HT use and risk of developing dementia. Follow-up time started with age at January 1, 1999 and participants were censored according to age at dementia diagnosis, age at date of death, age at date of lag in Kaiser membership (a lag in membership of 90 days or more), or age at the end of follow-up, June 1, 2008. Those in the never used HT category were the reference group in all models. We tested for a significant interaction of mid-life HT and late-life HT on dementia risk using a product term (midlife HT times late-life HT).
Models were adjusted for age (as time scale), education (high school, trade school, college 1–2 years, college 3–4 years and postgraduate, with grade school as reference), race (black, Asian, or other, with Caucasian as referent group), mid-life BMI (continuous variable), diabetes, hypertension, hyperlipidemia, stroke and hysterectomy status. Mid-life and late-life ascertainment of disease status for diabetes, hypertension, and hyperlipidemia (see midlife and latelife covariate section) were combined to create a time dependent covariate. Finally we performed a sensitivity analysis of HT and dementia risk stratified by stroke status, since stroke is a robust predictor of dementia, and prior studies have found HT use to increase risk of stroke. The study was approved by the Internal Review Board of Kaiser Permanente.
The average age of the women in mid-life was 48.7, and 27% of the sample was non – white (). Forty-five percent of the women (n=2454) did not take HT in mid or late-life (never users, median age 50), 25% (n=1384) were taking HT in mid-life only (mid-life users, median age 50), 12% (n=673) were on HT in late-life only (late-life users, median age 47.3), and 18% (n=993) were on HT both in mid and late-life (both users, median age 49). Black women were more likely to be non-users, while white women were more likely to be on HT both in mid and late-life. Those on HT in late-life only were more likely to have more children, report fewer miscarriages, and to have a diagnosis of hyperlipidemia and stroke (). Twenty-three women had an oophorectomy at baseline.
Characteristics and Co-Morbidities of the Participants by Hormone Status
Twenty –seven percent (N=1524) of the women were diagnosed with dementia between January 1,1999 and June 1, 2008 () and had a median age of 80.4 years at start of dementia follow-up (January 1, 1999). Since the majority of dementia cases were in women above median age at start of follow-up, frequency of dementia by the 4 hormone groups was examined stratified by median age. Women on HT in late-life only had the highest prevalence of dementia diagnoses (, 23% of women on late-life HT for those < age 80.4 years, p<.01; 36% of women on late-life HT for those ≥ age 80.4 years, p<.01). For both age groups, those on HT in mid-life only had the lowest prevalence of dementia diagnoses (20.9% for women <80.4 years. p<.01, and 31.6% for women > 80.4 years, p<.01).
Frequency of Dementia Cases by Hormone Therapy Status Stratified by Median Age in 1999
Age as time scale survival curves were performed to analyze the likelihood of dementia by HT timing. As seen in , those on HT in late-life only were the least likely to be dementia free (58%), while those taking HT in mid-life only had the highest likelihood of being dementia free (78%). Those on HT at both time points had very similar dementia risk as those never taking HT at the two time points, approximately 70% of both groups were dementia free at the end of the follow-up period ().
Age as Time Scale Kaplan Meier Survival Curves of Dementia Risk
There was a statistically significant interaction between mid-life and late-life HT use (p<.03) in association with dementia risk. Cox proportional hazard models with never HT users as the reference group showed significant associations between HT use and dementia risk. Those reporting HT use in mid-life only, had a reduced risk of dementia, while those reporting HT use in late-life only had an elevated risk of dementia. In a model fully adjusted for age (as time scale), education, race, BMI, number of children, diabetes, hypertension, hyperlipidemia, and stroke, mid-life HT use was associated with a 26% reduced risk of dementia, (HR=0.74, 95% CI, 0.58,0.94) (), while late-life HT use was associated with a 48% increased risk of dementia as compared to women not on HT (HR=1.48, 95% CI, 1.10,1.98). Additionally adjusting for hysterectomy status did not change the results by much (fully adjusted HRs: mid-life HT, HR=0.72, 95% CI 0.56, 0.91), late-life HT, HR= 1.45, 95% CI, 1.08,1.95), and both HT, HR=0.96, 95% CI 0.73, 1.26). Models excluding the twenty-three women with an oophorectomy were not different from the models that included them.
Cox Proportional Hazard Models of Hormone Use and Risk of Dementia
Stratification by stroke status revealed that the pattern of decreased risk of dementia associated with mid-life HT use was similar in magnitude for women regardless of stroke status, although not a significant effect for those without a stroke (). However the pattern of increased risk of dementia associated with late-life HT use was significantly stronger among women who had a stroke; a 63% fully adjusted increase in dementia risk for women with a stroke versus a 16% fully adjusted increase for those without a stroke ().
Cox Proportional Hazard Models of Hormone Use and Risk of Dementia Stratified by Stroke Status