Observational studies

Observational studies are aimed to explore the exposure-outcome relationship over a long period of time while providing information on multiple co-variables and confounders pertinent to the specific outcome and exposure. Table 3 summarizes the main findings from observational studies between HT use and the risk of cognitive decline and dementia.

Studies exploring the use of HT with AD have made the following conclusions: long-term postmenopausal HT use for ≥10 years decreased risk of AD if started early in menopause (Shao et al., 2012, Bove et al., 2014, Zandi et al., 2002b); high life-time exposure to endogenous estrogens protected against AD [Fox et al., 2013]; although one case-control study did not observe a protective association between HT and AD (Roberts et al., 2006), in other case-control studies, HT use has been associated with a lower risk of AD in the youngest age group (50-63 years) (Henderson et al., 2005), an effect that was independent of education and age at menopause (Waring et al., 1999).

Studies with other measures of HT use and with cognitive decline and dementia as the main outcome yielded the following results: 1. Increased lifetime exposure to endogenous estrogens improved cognitive functions (Hesson 2012, Rasgon et al. 2005); 2. Lifetime use of HT decreased cognitive decline (Carlson et al., 2001); 3. Current use of HT improved cognition (Steffens et al., 1999) and past and current HT users had better cognitive functions than non-users (Ghidoni et al., 2006); 4. Early use near menopause was more protective against cognitive decline than late use (Whitmer et al., 2011, Greendale et al., 2009, Galen Buckwalter et al., 2004, MacLennan et al., 2006); 5. HT users had better verbal memory, abstract reasoning, and visuospatial skills than non-users (Maki et al., 2011, Wharton et al., 2009a, Duff and Hampson 2000, Maki et al., 2001); 6. High serum estradiol levels at baseline were protective against cognitive decline and vice versa (Yaffe et al., 2000b, Yaffe et al., 2006); 7. The use of 17-β estradiol was more effective than CEE at improving verbal memory (Wroolie et al., 2011); 8. In a few studies, the use of HT was not protective against cognitive decline and dementia (Petitti et al., 2008, Kang et al., 2004a); 9. The protective effect of HT on cognition depends upon APOE ε4 status. In one study, the use of HT among APOE Ɛ4 negative women was protective against cognitive decline but not among APOE Ɛ4 carrier women (Yaffe et al. 2000a). In contrast, in another study, among current HT users, the risk of dementia was not increased significantly in the APOE Ɛ4 carrier women (Ryan et al. 2009).

The difference in results between observational and clinical studies may be attributable to differences in sample selection, duration of follow-up, dropout rate, type, duration, and formulation of HT, and time of initiation as well as the women’s baseline health statuses (Monk and Brodaty 2000).

26 Table 3: Observational studies examining the association between postmenopausal HT and risk of cognitive decline, dementia, and AD Study, Country, follow-up time

Sample features Information on hormone therapy

OutcomeCovariates Main results COHORT STUDIES Steffens et al. 1999, USA 2 years

2338 ≥65 yearsSelf-reported estrogen useGlobal cognition (3MS) in a structured interview APOE status, demographics, medical and gynecological history, lifestyle factors

Current estrogen use was associated with high 3MS score independently. Yaffe et al. 2000, USA 6 years

425 ≥ 65 yearsSerum concentration of estradiol and testosterone at baseline Cognition assessed at baseline and after 6 years using modified version of MMSE Demographic factors, medical history, gynecological history, lifestyle factors

High concentration of bioavail estradiol (endogenous estrogen) was associated with less likelih of developing cognitive impairment. Yaffe K 2000, USA 6 years

2716 ≥ 65 yearsSelf-reported current and past use of oral estrogens and progesterone Annual cognitive assessment (3MS) Demographic and lifestyle factors, internal carotid wall thickness, APOE status

APOE non-carrier women usin estrogen therapy currently had cognitive decline. Estrogen use was associated w less carotid wall thickening. Carlson et al. 2001, USA 5 years

2073 ≥65 yearsEver vs. never, past and present use of HT Global cognition (MMSE) APOE status, demographics, occupation history, psychiatric and medical history, education, calcium and multivitamins intake

Lifetime HT use improved glob cognition and decreased cogn decline over 3 years. Improvements were highest in oldest old. Zandi et al. 2002, USA 5 years

1889 Mean age 74.5 years Ever vs. never HT use and Former vs. current HT use Incident AD (using 3MS score) or informant based questionnaire Age, education, APOE status, history of calcium and multivitamin intake

Prior HT use was protective agai AD than current use unless latte exceeded >10 years. Kang et al. 2004, USA 6 years

13807 ≥70 yearsSelf-reported opposed or unopposed HT use TICS at baseline, verbal memory, category fluency, digit span backwards APOE status, demographics and lifestyle factorsNo significant cognitive benefits were observed for any type or duration of HT use.

27 Kok et al. 2006, UK1216 born in 1946 and examined at age 53

Annual postal questionnaires based information on HT use Home visits to assess reading speed and concentration, verbal memory Detailed menopause history, education, social class, smoking, BMI, cardiovascular disease

Postmenopausal cognitive declin more effectively explained by premenopausal cognitive stat and lifetime social class. Yaffe et al. 2006, USA 2 years

353 70-79 years Bioavailable estradiol (pg/ml) Global cognition (3MS), delayed verbal memory, executive function Age, race, sex, education, depression, weight, height, medical history, HT past use, APOE status

Lower estradiol levels at baselin resulted in cognitive decline an verbal memory impairment. Petitti et al. 2008, USA 4 years

2906 ≥75 years Self-reported and prescription based HT use Annual cognitive assessment (TICS-m) Age, education, race, medical history, time since menopause for HT use

Long term HT use was not protective against dementia. Petitti et al. 2008, USA 4 years

2906 ≥ 75 yearsSelf-reported HT use at baseline and prescription based HT use Annual cognitive assessment (TICS-m), medical record review

Age, education, race/ethnicity, medical historyNo protective effects of HT wer observed to prevent dementia Ryan et al. 2009, France 4 years

3130 >65 years Current, past, and never users of HT Duration and type of HT used Global function, visual memory, verbal fluency, verbal memory, psychomotor speed, executive function Age, medical history, age at menopause, BMI, education, marital status, depression, APOE status, coffee intake, anticholinergic drugs

Recent HT use improved verba fluency, working memory and psychomotor speed Current HT use decreased dementia risk for APOE Ɛ4 carri only. Greendale et al. 2009, USA 4 years

2342 42-52 years

Time spent in menopausal transition and HT use prior to and after menopause Processing speed, verbal memory, working memory Age, stage of menopause, race, education level, daily life activities, use of language

Cognitive difficulties during menopausal transition were recovered in post menopause HT use prior to last menstrual period had beneficial effect than later use. Whitmer et al., 2011, USA 34 years

5504 Midlife self- reported HT use Late life HT use assessed with pharmacy records Dementia diagnosis from electronic medical records between 1999- 2008 Age, race, education, medical history, number of children, BMI Women using HT in mid-life w protected against dementia. HT use in late age was detrimental

28 Shao et al. 2012, USA 11 years

1768 ≥65 yearsTime of initiation, duration and type of HT used Cognitive impairment (3MS) and AD dementia (NINCS-ADRDA criteria) Demographics, medical and gynecological history, lifestyle factors

Use of HT within 5 years after menopause and for ≥10 yrs decreased AD risk. Opposed HT started >5 yrs after menopause increased AD risk Bove et al. 2014, USA 18 years

1884 Mean age 78 years Self-reported information on type, duration and mode of HT use at baseline Dementia and AD diagnosis (NINCS- ADRDA), annual cognitive tests for multiple domains Detailed gynecological history, demographic factors, lifestyle factors, postmortem markers of AD pathology for 600 women

HT started within 5 years of per menopausal period and used fo >10 years protected against cognitive decline. CASE-CONTROL and CROSS-SECTIONAL STUDIES Waring 1999, USA Case-Control study

222 cases and controls each mean age 50 HT use ascertained from registers AD diagnosis ascertained from registers Age matched cases and controls, education, age at menopause, autopsy reports, breast and endometrial cancer, medical and reproductive history

HT protected against AD independent of education and at menopause. Duff and Hampson 2000, UK Cross sectional study

96 45-65 years Self reported HT useWorking memory, Explicit memory Age, education, socioeconomic status matched groups, age at menopause, medical history, type dose and schedule of HT use

HT users performed better in verbal and spatial working mem tasks than non-users. Maki et al. 2001, USA Cross sectional

184 50-89 years Oral or transdermal estrogen HT with or without progesterone Verbal memory, figural memory, mental rotations, attention, working memory Age, education, annual income, type of HT, duration of treatment, self-reported health status, depression

HT users scored significantly bet than never users in verbal mem test, encoding, and retrieval o words. Buckwalter et al. 2004, USA Case-control study

105 ≥ 75 yearsHT use assessed from prescription register Learning and memory (verbal and nonverbal, attention), executive functioning (working memory, language) Age, telephone interview of cognitive status at baseline, education, ethnicity, depression, past HT use and duration

HT not beneficial in cognitive performance among older ag group. Henderson et al. 2005, USA

971 women aged >60 yearsSelf-reported estrogen use from controls and from AD diagnosis obtained from memory clinicsAge, education, ethnicity, APOE status, alcohol intake, smoking, medical history HT use reduced AD risk amon youngest age group (50-63 years)

29 Case-Control study primary informants of AD cases Rasgon et al. 2005, Sweden Cross sectional

6604 twins aged 65- 84 years Endogenous and exogenous hormone exposure Cognitive impairment assessed in one interview through TELE, a brief telephone cognitive screening test Age, parity, age at menarche and menopause, length and type of HT, general health, physical activity, occupation, education

Risk of cognitive impairment decreased significantly with increase in length of lifetime estrogen exposure. MacLennan et al. 2006, Australia Cross sectional

428 >60 yearsSelf reported HT use MMSE, attention and concentration, verbal expression, verbal learning Age, education, hysterectomy status, cardiovascular disease history, BMI, smoking and alcohol intake history, mood

Early initiation of HT was benefici for selective cognitive domain late HT use was detrimental. Ghidoni et al. 2006, Italy Cross sectional

83 women aged > 50 years Current, past and never use of HT

Global cognition (MMSE), memory, visuo-spatial ability, language, intelligence, attention assessed in neuropsychological test battery over 60-90 minutes Age, education, duration of HT (months), age at and type of menopause, family history of dementia, 40 women underwent 3D high resolution MRI (total intracranial volume)

Past users performed better th never users in linguistic, attentiv and planning abilities. Current users performed bette verbal memory. Estrogen HT users had greater gr matter volumes than nonusers Roberts et al. 2006 USA Case-Control study

264 AD cases 264 controlsMedical records based use of oral or parenteral HT AD diagnosis taken from medical record linkage system Age at start of HT, time since menopause, age at menarche, type of menopause, reproductive span, medical history, education

No significant association observ between HT use and AD. W. Wharton et al. 2009, USA Case-Control study

213 51-93 years Self reported HT users and non-users

Global cognition (3MS), verbal fluency, verbal memory (CERAD), word list, attention (Stroop test) in 1 hour cognitive test battery Self-reported health questionnaire, age, education, depression, alcohol intake, smoking, MMSE , medical history

HT users performed better than non-users on measures of verba memory and abstract reasonin Maki et al. 2011, Australia Cross sectional

34 mean age 60 years

Daily diary based users and non-users of HT Verbal memory, face memory, functional MRI during verbal and figural recognition Age, education, moodWomen using HT in perimenopause performed bett on verbal memory tasks than no users and it was evident on functional MRI.

30 Wroolie et al. 2011, USA Cross sectional study

68 49-68 years at risk of AD

HT use ascertained through pharmacy records

Working memory, processing speed, verbal memory, visual memory, and executive functioning Risk factors of AD, education, years of endogenous estrogen, age at menopause, BMI, type of menopause

Women using estradiol perform better in verbal memory than CE users. Hesson et al. 2012, Canada Cross sectional

50 Mean age 69.3Index of cumulative estrogen exposure (ICEE) Prospective and retrospective memory, Logical Memory in a single test session History of HT use, age at menarche and menopause, BMI, time since menopause, nulliparity, duration of breast feeding, age, education

ICEE significantly predicted prospective memory task performance but not retrospectiv memory. Fox et al. 2013, UK Cross sectional

133 70-100 yearsTotal lifetime exposure to estrogen (months) Alzheimer’s dementia assessed with Clinical Dementia Rating scale in 60-90 minute interview Age, family history of dementia, parity, age at first birth, any HT use, hysterectomy, bilateral oophorectomy, religion, education, smoking, alcohol intake

Longer reproductive span, age at first delivery, and more mon in lifetime in pregnancy were protective against AD. Abbreviations:AD: Alzheimer’s disease;APOE: Apolipoprotein E; 3MS: Modified Mini Mental State examination; MMSE: Mini Mental State examination hormone therapy; BMI: body mass index; NINCS-ADRDA: National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer’s diseas and Related Disorders Association; MRI: Magnetic resonance imaging; ; CEE: conjugated equine estrogens; CERAD: Consortium to Establish Register Alzheimer’s disease; TICS-m: Telephone Interview of Cognitive Status-modified (TICS-m); ICEE: index of cumulative estrogen exposure

In document Hormone therapy and the risk of dementia, cognitive decline and Alzheimer's disease (sivua 51-57)