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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 62:1035-1041 (2007)
© 2007 The Gerontological Society of America

Endogenous Sex Hormones as Risk Factors for Dementia in Elderly Men and Women

Giovanni Ravaglia, Paola Forti, Fabiola Maioli, Luciana Bastagli, Fausta Montesi, Nicoletta Pisacane, Martina Chiappelli, Federico Licastro and Christopher Patterson

1 Department of Internal Medicine, Cardioangiology, and Hepatology, University of Bologna, Italy.
2 Department of Experimental Pathology, University of Bologna, Italy.
3 Department of Medicine, McMaster University, Hamilton, Canada.

Address correspondence to Professor Giovanni Ravaglia, MD, Department of Internal Medicine, Cardioangiology, and Hepatology, University Hospital S. Orsola, Malpighi, Via Massarenti, 9–40138 Bologna, Italy. E-mail: ravaglia{at}med.unibo.it


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. The associations of endogenous sex hormones with risk of dementia in the elderly population are not well known.

Methods. The relationship of baseline serum total estradiol (E2) and free testosterone (FT) to 4-year risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) was examined in a dementia-free, population-based cohort of 433 women (mean age 74 years) and 376 men (mean age 73 years). Multivariable proportional hazards regression was used to adjust for sociodemographic and lifestyle variables, body mass index, apolipoprotein E genotype, cardiovascular conditions, and homocysteinemia.

Results. Dementia developed in 71 women (46 AD, 21 VaD) and 39 men (23 AD, 12 VaD). In women with high E2 (serum E2 ≥ 10 pg/mL), the multivariable-adjusted hazard ratio (HR) for dementia was 1.75 (95% confidence interval [CI], 1.06-2.89). The corresponding multivariable-adjusted HR for AD was 1.94 (95% CI, 1.04-3.61), whereas no association was found for VaD. No association with dementia was found for serum FT in women and for either serum E2 or FT in men.

Conclusion. High serum E2 is an independent predictor for dementia and AD in elderly women.

Evidence from in vitro and animal studies for beneficial effects of sex hormones on the brain (1,2), studies of endogenous sex hormones and cognition in humans (1–6), and studies of hormone replacement therapy (HRT) in older women (1,2,7) suggest that low levels of endogenous sex hormones may be a risk factor for Alzheimer's disease (AD).

However, a Cochrane meta-analysis of five randomized controlled trials failed to find evidence that HRT can maintain cognitive function for up to a year in postmenopausal women with AD (8). Moreover, in the Women's Health Initiative Memory Study (WHIMS) (9), 4-year risk of all dementia types was doubled among women in the estrogen-plus-progestin-therapy arm with respect to the placebo group.

Only two longitudinal studies focused on endogenous sex hormones and dementia risk in elderly persons. According to one study, high estrogen was associated with vascular dementia (VaD) but not AD in elderly women, whereas it was not associated with either dementia type in men (10). In another investigation, older men with a low testosterone level had an increased risk of AD (11).

In the present study, baseline serum total estradiol (E2) and free testosterone (FT) were examined in relation to 4-year risk of dementia and dementia subtypes in an elderly Italian cohort.


   METHODS
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 Abstract
 Methods
Results
 Discussion
 References
 
Study Population
Participants are from the Conselice Study of Brain Aging (CSBA), a population-based prospective survey described in detail elsewhere (12). After approval from our institutional review board, written informed consent was obtained from all participants.

Briefly, in 1999–2000, 1016 (75%) of the 1353 individuals aged 65 years or older residing in the Italian municipality of Conselice (Emilia Romagna region, Northern Italy) underwent the baseline examination, including (a) a standardized interview with the participant and an informant (a relative or any other knowledgeable person) for collection of sociodemographic information and medical history; (b) physical examination; and (c) fasting venous blood drawing. Data on cognitive status at follow-up examination in 2003–2004 (mean follow-up time 3.8 ± 0.8 years) and serum samples for sex hormone measurement were available for 809 of the 925 individuals who, at baseline, were free of dementia and had not taken sex hormone replacement or antihormone therapies in the previous 6 months. Figure 1 reports a flow chart detailing the derivation of the incidence sample.


Figure 01
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  		Figure 1. Flow chart detailing the derivation of the incidence study sample

 
Case Finding
For 684 survivors who agreed to be re-evaluated, identification of incident dementia cases in 2003–2004 followed the same procedure used to identify prevalent cases at baseline (12). The Italian version of the Mini-Mental State Examination (MMSE) with standardized age- and education-specific adjustment coefficients (13) was used for cognitive screening. Participants with an MMSE score below 24 were further tested with the Mental Deterioration Battery (14). Whenever recent neuroradiological data were not available, participants were scheduled for a noncontrast computed tomography brain scan. Standardized information from several sources (the participants themselves, relatives, general practitioners, and death certificates) was considered reliable to define the occurrence of dementia among 125 individuals who died before follow-up examination or who refused to undergo it. These participants were older than reassessed participants (76.2 ± 7.8 years vs 73.0 ± 6.0 years, p <.001), but did not differ in gender, education, and sex hormone levels.

Written informed consent for collection and use of this information was obtained from the participants or their relatives. Dementia was defined using Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) clinical criteria (15). AD was diagnosed using National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria (16). VaD was diagnosed using NINDS-AIREN criteria (17). Participants who were positive at screening and those with cognitive impairment at neuropsychological testing but no clinical evidence of dementia were classified as "mild cognitive impairment" (MCI) (18) but, for the purposes of this study, were included in the no dementia group.

Sex Hormone Assays
Serum samples for sex hormone assay were stored at –70°C until analyses were performed (storage duration up to 48 months). Total E2, including both the protein-bound and the free, bioavailable form of the hormone, was measured by direct chemiluminescence technology (automatized ADVIA Centaur estradiol-6 III assay; Bayer Diagnostics, Tarrytown, NY). The detection limit was 10 pg/mL. Serum FT was measured by radioimmunoassay (Adaltis, Bologna, Italy). The detection limit was 0.2 pg/mL. Mean intra- and interassay coefficients of variation for both were about 7%.

Covariates
The following variables were extracted from the baseline database: age, age at menopause, education (≤ 3 vs > 3 years of formal education, because of the sample's poor schooling), smoking status (never smokers vs ex smokers and current smokers), cardiovascular diseases (myocardial infarction, angina, peripheral vascular disease, and congestive heart failure), and body mass index (weight in kilograms divided by the square of the height in meters).

Apolipoprotein E (APOE) {varepsilon} allele genotyping was performed on genomic DNA by using polymerase chain reaction as previously described (19). Baseline hyperhomocysteinemia [plasma total homocysteine > 15 µmol/L (20)] was included because of its association with AD risk (19,21), vascular risk (22), and low estrogen status (20,23). Baseline serum creatinine, folate, and vitamin B12 were taken into account because renal function and B vitamin deficiencies are the main determinants of homocysteinemia in the elderly population (20). Plasma total homocysteine concentrations were measured in frozen plasma samples (storage duration up to 12 months) using the automatized IMx fluorescence polarization immunoassay (Abbott Laboratories, Abbott Park, IL).

Folate and vitamin B12 were measured in fresh serum using by immunoelectrochemiluminescence analysis as reported elsewhere (19). Serum creatinine was measured by the Jaffé method, adapted for autoanalyzers.

Statistical Analysis
Variables are presented as mean ± standard deviation (continuous) or number and percentage (categorical) except for plasma homocysteine and serum folate and vitamin B12 which, because of their highly skewed distribution, were analyzed as natural-log-transformed values and reported as geometric mean (95% confidence interval [CI]).

Cox proportional-hazards regression was used to investigate serum E2 and FT in relation to risk of all-cause dementia, AD, and VaD. Models were run separately for women and men and were adjusted for age, education, APOE genotype, smoking status, cardiovascular disease, stroke, body mass index, hyperhomocysteinemia, serum creatinine, serum folate, and vitamin B12. Date of dementia onset was estimated as the midpoint of the time interval from baseline study until follow-up or death.

Because the literature suggests a U-shaped relationship between sex hormone concentrations and cognition (2), E2 and FT were first entered into an unadjusted Cox model for all-cause dementia risk as gender-specific quartiles. The top and third E2 quartiles of women were compared to undetectable values because the median of the distribution fell at the lowest detectable serum E2 concentration (10 pg/mL). In the absence of evidence for a U-shaped association, sex hormones were analyzed as "high" versus "low" concentrations (defined as > and ≤ the gender-specific median, respectively).

Student t tests, Mann–Whitney U tests, and chi-square tests were used for comparisons between groups. Statistical analyses were performed using SYSTAT10 (SPSS Inc., Chicago, IL).


   RESULTS
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 Abstract
 Methods
 Results
Discussion
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Characteristics of women and men by cognitive status at follow-up are reported in Tables 1 and 2. Among women there were 71 cases of incident dementia (46 AD, 21 VaD, and 4 from other causes) in 3.9 ± 0.7 years of follow-up. Among men there were 39 cases of incident dementia (23 AD, 12 VaD, and 4 from other causes) in 3.8 ± 0.8 years of follow-up. Incident dementia cases were generally older and less educated than cognitively normal participants and more frequently had MCI, hyperhomocysteinemia, and low serum folate levels. Women with incident dementia and AD had higher E2 than cognitively normal women had, whereas no difference was found for FT. No difference in sex hormone levels was found between men who did and did not develop dementia.


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  		Table 1. Baseline Characteristics of the Cohort by Cognitive Status at Follow-Up: Women (N = 433).

 

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  		Table 2. Baseline Characteristics of the Cohort by Cognitive Status at Follow-Up: Men (N = 376).

 
Table 3 reports the number of incident dementia cases across gender-specific quartiles of sex hormones. Figure 2 shows the unadjusted hazard ratios (HR) and 95% CI values for all-cause dementia. There was no reason to assume a U-shaped relationship with all-cause dementia risk for E2 in women and FT in men. By contrast, on the basis of a visual inspection of the plot, FT in women and E2 in men were additionally analyzed after regrouping the values into "low," "intermediate," and "high" (defined, respectively, as below, in the range of, and above the corresponding gender-specific interquartile range).


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  		Table 3. Incident Dementia Cases Across Gender-Specific Quartiles of Serum Estradiol and Free Testosterone.

 

Figure 02
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  		Figure 2. Unadjusted hazard ratios and 95% confidence intervals for all-cause dementia plotted on a logarithmic scale across gender-specific quartiles of serum total estradiol and free testosterone. Data are for 433 women and 376 men; the number of incident dementia cases was 71 for women and 39 for men. Women with undetectable serum total estradiol (< 10 pg/mL) were grouped together

 
Table 4 reports the associations of sex hormones with dementia risk in women. High E2 level was associated with risk of all-cause dementia and AD, but not with risk of VaD, even after multivariable adjustment. After exclusion of seven women who reported use of HRT before the 6-month interval preceding the study (range 2–5 years), multivariable-adjusted HR (95% CI) was 1.75 (1.05–2.88) for all-cause dementia, 1.94 (1.04–3.60) for AD, and 1.74 (0.61–4.40) for VaD. After exclusion of 32 women with baseline MCI, multivariable-adjusted HR (95% CI) was 1.69 (0.96–2.97) for all-cause dementia, 2.10 (1.03–4.26) for AD, and 1.91 (0.94–3.92) for VaD. After exclusion of 66 women who did not undergo formal cognitive reassessment at follow-up, multivariable-adjusted HR (95% CI) was 1.74 (1.04–2.93) for all-cause dementia, 1.94 (1.01–3.74) for AD, and 1.91 (0.74–4.90) for VaD. The corresponding multivariable-adjusted HR (95% CI) for hyperhomocysteinemia was 2.02 (1.07–3.80) for all-cause dementia, 2.15 (1.16–4.01) for AD, and 3.26 (0.93–11.40) for VaD.


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  		Table 4. Risk of All-Cause Dementia and Alzheimer's Dementia Associated With Serum Total Estradiol and Free Testosterone in Elderly Women.

 
No association was found between FT and dementia in women and between sex hormones and dementia in men (Table 5). Results did not change after exclusion of women reporting past use of HRT, MCI participants, and those who did not undergo formal reassessment at follow-up (data not shown).


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  		Table 5. Risk of All-Cause Dementia and Alzheimer's Disease Associated With Serum Total Estradiol and Free Testosterone in Elderly Men.

 
Baseline data about alcohol and caffeine intake, serum cholesterol, serum thyrotropin, and hypertension were also available, but additional adjustment for these variables did not alter the study results as well as adjustment for sex hormones and plasma total homocysteine as continuous log-transformed variables (data not shown).


   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The main finding of this study is that, in postmenopausal women, high E2 was associated with risk of AD but not of VaD, independent of possible confounders. Results from cross-sectional studies are inconsistent, with the E2 of AD female patients reported to be higher, unchanged, and even decreased with respect to controls (24). A longitudinal case–cohort investigation using data from the Rotterdam Study (10) reported an association between high E2 and VaD, but not AD, in postmenopausal women. Features of the Rotterdam cohort that might explain the difference with our findings are the small number of VaD cases (only 12), actually precluding multivariable-adjusted analyses, and the relative homogeneity in low E2 concentrations, which could have prevented enough variability to detect an association with AD.

Our findings agree with the inverse association between E2 and cognitive function found in cross-sectional population-based studies of older women (3,4). They also agree with the increased dementia risk reported for the postmenopausal women in the estrogen-plus-progestin arm of the WHIMS trial (9). In another sample of postmenopausal women, 6-year risk of cognitive impairment was not associated with total E2 (24), and even decreased among women with low free E2 (5). Cognitive impairment, however, was measured using a short version of the MMSE, which is an instrument for cognitive screening but not for dementia diagnosis (25).

It is not clear how estrogen may increase dementia risk, especially in the face of the possible beneficial effects on the brain shown by in vitro studies (neurotrophic and antioxidant activity, decreased beta-amyloid accumulation, enhanced neurotransmitter function) (1). A possible hypothesis is that estrogen might increase the risk of AD in women through its procoagulant activities (1,3). Indeed, cerebrovascular damage often coexists and overlaps with AD (26). However, the lack of a similar association with VaD risk argues against such an interpretation. Another possible mechanism is through activation of inflammatory pathways. HRT increases circulating inflammatory markers in postmenopausal women (27), and chronic low-grade inflammation is suggested to play a role in AD (28). Of course, it cannot be excluded that, in younger women, estrogen might have different and even beneficial effects on cognition (29). In agreement with previous studies of cognitive function (24), no association was found between FT and dementia in women.

No association was found between sex hormones and dementia risk in elderly men. Previous cross-sectional studies produced inconsistent results (2), whereas longitudinal investigations reported no association with E2 (9) and an increased risk of AD in men with low FT (9). The latter investigation had a longer follow-up time (19.1 years) than did the CSBA, but the cohort age range was from 32 to 87 years.

Strengths of our study are the relatively large population, the small number of women reporting previous use of estrogen replacement therapy, and the concurrent investigation of estrogen and androgens.

This study has also several limitations. First, the study was not specifically designed for the purpose of examining the relationship between sex hormones and dementia, only total E2 and FT were measured, measurements were based on a single baseline assay, and, owing to budgetary constraints, free E2 was not measured. Second, serum E2 concentrations below 10 pg/mL occurred in about one half of the women in our sample. However, similar prevalences were found in other studies of postmenopausal women using comparable assays (24,30,31). Third, sex hormone production in men does not decrease as abruptly as in women, so a longer follow-up time might be required to find significant associations. Fourth, the study design cannot establish whether E2 is actually a risk factor or a consequence of dementia, because the preclinical dementia process may start a decade or more before diagnosis. Indeed, incident dementia cases had a higher baseline prevalence of MCI than did participants who did not develop dementia. However, exclusion of MCI participants did not affect results. Finally, the inclusion in the study of 125 participants who did not undergo formal assessment at follow-up might be questioned. However, informant reports are acknowledged to be reasonably valid for AD diagnosis for patients who cannot undergo a formal assessment (32), and this diagnostic approach has been previously used in other epidemiologic studies of dementia (33). Although we cannot exclude the possibility that milder dementia cases may have been misclassified as cognitively normal, exclusion of the participants without formal reassessment did not affect results.

Conclusion
Our study adds information to the knowledge about the association between endogenous sex hormones and cognitive function in older persons, reporting that increased serum E2 may increase risk of AD in elderly postmenopausal women.


   Acknowledgments
Top
 Abstract
 Methods
 Results
 Discussion
 References
 
This study was supported by grants from the Italian Ministry of Education, University and Scientific Research (ex-60% fund for basic oriented research).


   Footnotes
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 Methods
 Results
 Discussion
 References
 
Decision Editor: Darryl Wieland, PhD, MPH

Received July 26, 2006

Accepted November 20, 2006


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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