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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1072
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 1168-1172
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Interaction between Testosterone and Apolipoprotein E {epsilon}4 Status on Cognition in Healthy Older Men

Melanie S. Burkhardt, Jonathan K. Foster, Roger M. Clarnette, S. A. Paul Chubb, David G. Bruce, Peter D. Drummond, Ralph N. Martins and Bu B. Yeap

School of Psychology (M.S.B., P.D.D.), Murdoch University, Murdoch, Western Australia 6150, Australia; Sir James McCusker Alzheimer’s Disease Research Unit (M.S.B., J.K.F., R.M.C., R.N.M.), School of Exercise, Biomedical, and Health Sciences, Edith Cowan University, and School of Psychiatry and Clinical Neurosciences, University of Western Australia, Hollywood Private Hospital, Nedlands 6009, Western Australia; Neurosciences Unit (J.K.F.), Health Department of Western Australia, East Perth Western Australia 6004, Australia; Departments of Geriatric Medicine (R.M.C., D.G.B.), Biochemistry (S.A.P.C.), and Endocrinology and Diabetes (B.B.Y.), Fremantle Hospital, Fremantle, Western Australia 6959, Australia; and School of Medicine and Pharmacology (R.M.C., D.G.B., B.B.Y.), University of Western Australia, Fremantle Hospital, Fremantle, Western Australia 6959, Australia

Address all correspondence and requests for reprints to: Professor Ralph N. Martins, Sir James McCusker Alzheimer’s Disease Research Unit, School of Exercise, Biomedical, and Health Sciences, Edith Cowan University, and School of Psychiatry and Clinical Neurosciences, University of Western Australia, c/o Hollywood Private Hospital, Nedlands, 6009 Western Australia, Australia. E-mail: r.martins{at}ecu.edu.au.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Reduced testosterone levels have been implicated as a potential causative factor in cognitive decline with older age. Men who possess the apolipoprotein E (APOE) {epsilon}4 allele have an increased risk of developing Alzheimer’s disease; however, no studies have examined whether the influence of testosterone on cognition in healthy older men may be modulated by this genetic predisposition.

Objective: The objective of the study was to investigate the association between serum testosterone concentrations and cognitive performance in healthy older men, taking into account APOE {epsilon}4 status.

Design: This was a cross-sectional study conducted from 2003 to 2004.

Setting: The study population consisted of community-dwelling males residing in Perth, Western Australia.

Participants: Healthy men over 55 yr, free of cognitive impairment and dementia (n = 45), were included in the study.

Main Outcome Measures: Participants had fasting early morning blood samples for testosterone and SHBG and were assessed for mood as well as indices of general cognition, verbal and visual memory, executive functioning, working memory, and attention.

Results: There was a significant interaction between calculated free testosterone (FT) and APOE {epsilon}4 on general cognition (P = 0.01) and executive functioning, working memory, and attention (P < 0.01). Higher levels of FT were associated with better general cognition in non-{epsilon}4 carriers (P = 0.01). By contrast, in {epsilon}4 carriers higher FT levels were associated with lower scores on tests of executive functioning, working memory, and attention (P = 0.02). In men at increased risk for Alzheimer’s disease, higher testosterone levels were not associated with better cognitive function.

Conclusions: Cross-sectional and prospective studies of testosterone and cognition in older men should take into account APOE {epsilon}4 status.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
LOWER TESTOSTERONE concentrations have been associated with lower scores on tests of cognitive ability (1, 2) and the subsequent development of Alzheimer’s disease (AD) (3). Testosterone deficiency modulates neuronal processes capable of increasing the risk for AD (4), and beneficial effects of testosterone supplementation have been reported on specific parameters of cognition in older men (5, 6). The apolipoprotein E (APOE) {epsilon}4 allele is thought to be the major genetic risk factor for AD (7) and may independently modulate normal age-related cognitive change (8). An association among low testosterone, APOE {epsilon}4, and AD has been reported (9), but it is not known whether testosterone and APOE {epsilon}4 interact to modulate cognition in men before the development of AD or whether differential effects of testosterone on cognition exist that are influenced by the absence or presence of {epsilon}4. We investigated the association among testosterone concentrations, genetic risk for AD, and cognitive abilities in healthy older men.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Our institutional ethics committee approved this study and informed consent was obtained from participants. Community-dwelling men over 55 yr of age with no history of cognitive impairment, dementia, or other major medical illness were recruited. Exclusion criteria were hormone-suppressive therapy, testosterone therapy, medications known to affect bone metabolism within the past 3 months, significant prostate disease, abnormal liver function, hypothyroidism, major sleep disturbance, consumption of alcohol greater than 21 U/wk, psychiatric disorders, stroke, head injuries, scores 80 or less on the Cambridge Cognitive Assessment-revised (CAMCOG-R) (10) (identifying frank cognitive deficits), and 1.5 SD or greater below the mean for age on measures of verbal learning and memory (identifying mild cognitive impairment). After these exclusions there were 45 healthy men studied.

Procedures

Information concerning: current medical problems, medications, lifestyle factors, and years of formal education (cumulative years of primary, secondary, and tertiary education) were obtained, and blood pressure and body mass index (kilograms per square meter) was measured. Blood samples were collected between 0830 and 1030 h after overnight fasting. A standard breakfast (energy value 938 kJ) was provided before cognitive testing of constructs cited as relevant in the AD literature (11) and parameters influenced by testosterone concentrations (1, 2, 5, 6).

Biochemical assessments. Total testosterone concentrations were determined by coated tube RIA (Coat-A-Count, Diagnostic Products Corp.-BioMediq, Doncaster, Australia) with coefficient of variation being 8.9% at 2.5 nmol/liter and 8.5% at 14 nmol/liter. SHBG concentrations were determined via chemiluminescent immunoassay on an Immulite 2000 analyzer (Diagnostic Products Corp.-BioMediq) with coefficient of variation of 6.8% at 5.1 nmol/liter and 9.3% at 82.5 nmol/liter. Free testosterone (FT), specifically the fraction not bound to either SHBG or albumin, was calculated using a previously validated method (12).

APOE genotyping. Peripheral blood leukocyte DNA was extracted and APOE genotyping was performed as previously described (13).

Mood assessments. Depressive symptomatology was assessed via the Geriatric Depression Scale (14). Current anxiety levels were assessed via the State Anxiety Scale from the Spielberger State Trait Anxiety Inventory (15).

Neuropsychological tests

The National Adult Reading Test (16) was administered to derive an estimate of full-scale intelligence quotient (FSIQ) to control for differences in reading and estimated intellectual ability. The following tests were administered to obtain the listed cognitive constructs:

1. General cognition. CAMCOG-R (10) total score was analyzed to obtain an index of performance on orientation, memory, language, praxis, attention, tactile perception, calculation, abstract thinking, and visual perception tasks.

2. Immediate memory. Immediate recall for verbal information on Wechsler Memory Scale-Third Edition (WMS-III) (17) Wordlists and visual information on the visual reproduction (VR) subtests was analyzed.

3. Delayed memory. Comprised delayed recall, recognition, and percentage retention of verbal and visual information over a 25-min delay period (via the WMS-III Wordlists and VR subtests respectively). Scores on VR copy condition were used to control for differences in visuospatial ability between participants and as a statistical covariate in the visual memory data analyses.

4. Executive functioning, working memory, and attention (EFWMA). The Delis and Kaplan Executive Function System (D-KEFS) Color-Word Interference Test (18), color-naming, word-reading, inhibition, and inhibition-switching components were administered in series to obtain measures of executive functioning. Completion times for inhibition and inhibition switching were analyzed. To assess attention and working memory, total correct responses on the WMS-III letter number sequencing (17) were analyzed.

5. Verbal fluency. Total correct responses on the D-KEFS verbal fluency test (18) (letter fluency, category fluency, and category switching conditions) and the percentage switching accuracy and errors made across all three conditions were analyzed.

A priori composites were calculated for each construct by converting raw scores for each participant on each test to age-adjusted scaled scores according to established norms (17, 18) and averaging the scaled scores. Composites reflecting broader constructs are more appropriate measures of cognitive ability and exhibit higher reliability than the individual components represented by single neuropsychological tests (19). These constructs were used as dependent variables in hierarchical linear regression analyses to examine the FT by APOE {epsilon}4 status interaction on cognition.

Statistical analyses

Data were analyzed using the Statistical Package for Social Sciences (version 11.5; SPSS Inc., Chicago, IL). Cohort characteristics were explored via one-way ANOVA for continuous data and using the Pearson method for 2 x 2 contingency tables ({chi}2) for categorical data. Homogeneity of variance and normality of data distributions were evaluated for FT and neuropsychological data in the groups [{epsilon}4 carriers ({epsilon}4+) vs. noncarriers ({epsilon}4–)]. Analysis of covariance/multivariate analysis of covariance (MANCOVA) was conducted to compare the effect of {epsilon}4 status (absence vs. presence) on FT, measures of mood, and cognitive performance, separately. Where appropriate, age and/or VR total copy score served as statistical covariates. The interaction between FT and {epsilon}4 status on composites of cognitive functioning was further examined via hierarchical linear regression analyses. Main effects involving FT concentrations were subsequently explored via Pearson’s correlation coefficient (r).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Characteristics of the cohort stratified by {epsilon}4 status are reported in Table 1Go. The {epsilon}4+ group was significantly older than the {epsilon}4– group [F(1, 43) = 5.75, P = 0.02]. The groups were similar for years of education, estimated FSIQ, body mass index, blood pressure, cigarette and alcohol use, current medications, and medical history. SHBG was higher in the {epsilon}4+, compared with {epsilon}4– group (44.4 ± 16.4 vs. 34.5 ± 14.0 nmol/liter, P = 0.04); however, FT was similar in both groups (0.27 ± 0.06 vs. 0.26 ± 0.07 nmol/liter, respectively).


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  		TABLE 1. Characteristics of healthy older men stratified by APOE {epsilon}4 status

 
Evaluation of group differences

Analysis of covariance was performed using FT as the dependent variable and {epsilon}4 status as the independent variable, with age as a statistical covariate. Age significantly influenced FT [F(1, 42) = 8.79, P = 0.01]. After adjusting for age, there was no significant effect of {epsilon}4 status on FT [F(1, 42) = 2.95, P = 0.09]. Unadjusted group means and SDs for {epsilon}4+ and {epsilon}4– groups for FT are presented in Table 1Go.

Mood

MANCOVA was performed to examine group differences on anxious and depressed mood. After adjusting for age, there was no significant effect of {epsilon}4 status on depressed and anxious mood (F(2, 41) = 1.18, P = 0.32). The statistical covariate age did not influence mood (F(2, 41) = 0.08, P = 0.92).

Cognitive performance

Separate MANCOVAs were performed using the individual measures of cognitive functioning as dependent variables, with age and VR total copy score as statistical covariates where appropriate. The {epsilon}4+ and {epsilon}4– groups performed similarly on general cognition (CAMCOG-R total score), visual memory (WMS-III VR immediate and delayed recall, percentage retention, and recognition indices), EFWMA (WMS-III letter number sequencing total recall and D-KEFS inhibition and inhibition-switching completion times), and verbal fluency (D-KEFS verbal fluency test indices).

Significant group differences emerged on verbal memory performance. MANCOVA was performed using raw scores on the WMS-III Wordlists immediate and delayed recall, percentage retention, and recognition indices as dependent variables. Age significantly influenced these dependent variables [F(4, 39) = 3.42, P = 0.02]. After adjusting for age, the overall MANCOVA was significant with respect to the influence of {epsilon}4 status [F(4, 39) = 3.22, P = 0.02] on these four measures of verbal memory. Because the overall MANCOVA was significant, subsequent analysis of each individual dependent variable showed significant differences in scores between {epsilon}4+ and {epsilon}4– groups, on delayed recall [F(1, 42) = 9.47, P < 0.01] and percentage retention [F(1, 42) = 8.31, P < 0.01] indices of the WMS-III Wordlists.

The interaction between {epsilon}4 and FT on cognitive performance in the cohort was explored via hierarchical linear regression analyses, using FT, {epsilon}4 status, and {epsilon}4 x FT as predictors of the following: 1) CAMCOG-R total score; 2) immediate memory; 3) delayed memory; 4) EFWMA; and 5) verbal fluency constructs. Hierarchical linear regression models are presented in Table 2Go. In line with the previous MANCOVA analyses, {epsilon}4 status was significantly related to delayed memory performance. The {epsilon}4 x FT interaction was significantly related to performance on the CAMCOG-R and EFWMA. These {epsilon}4 x FT interactions were subsequently explored within {epsilon}4+ and {epsilon}4– groups by calculating separately the correlation coefficient (r).


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  		TABLE 2. Hierarchical linear regression models for composites of cognitive constructs

 
The linear relationship between CAMCOG-R scores and FT within the {epsilon}4– and {epsilon}4+ groups is summarized in Fig. 1Go, A and B, respectively. CAMCOG-R scores positively correlated with FT (r = 0.46, n = 29, P = 0.01) in the {epsilon}4– group. There was significant negative correlation between FT concentrations and EFWMA in the {epsilon}4+ group (r = –0.58, n = 16, P = 0.02), as shown in Fig. 1Go, C and D.


Figure 1
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  		FIG. 1. Scatterplots of calculated FT vs. composites of cognitive constructs. Regression line and 95% confidence intervals as well as Pearson correlation coefficient (r) are shown. A, FT vs. CAMCOG-R scores for the {epsilon}4– group. B, FT vs. CAMCOG-R scores for the {epsilon}4+ group. C, FT vs. the EFWMA composite for the {epsilon}4– group. D, FT vs. the EFWMA composite for the {epsilon}4+ group.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
We systematically investigated the interaction between {epsilon}4 status and testosterone concentrations on cognition in apparently healthy older men. No difference in FT between the groups was noted in this cohort. Consistent with previous findings (20), we observed that APOE {epsilon}4 carriers had lower scores on delayed recall for verbal information compared with non-{epsilon}4 carriers.

The novel finding is the interaction between FT and {epsilon}4 status on general cognition and EFWMA. In cognitively healthy older men without the {epsilon}4 allele, FT levels were positively correlated with general cognitive ability (i.e. CAMCOG-R scores). By contrast, in men who possess the {epsilon}4 allele, FT levels correlated negatively with EFWMA. These statistically significant observations are of potential clinical relevance as testosterone supplementation has been postulated to have beneficial effects on cognition (5, 6); however, this was not addressed here. Because higher testosterone concentrations were associated with lower performance on EFWMA in {epsilon}4 carriers, testosterone supplementation may not be beneficial in this group (who are at higher relative risk for AD). It may be necessary to stratify men by {epsilon}4 status when examining the relationship between testosterone and cognition or when designing interventional trials of testosterone replacement for the prevention of cognitive decline in older men.

Particular strengths of this study were the careful case selection, allowance for potential confounders including mood, detailed neuropsychological assessments, and the examination of a cohort free of cognitive impairment and dementia. Additionally, composite measures of cognitive performance were determined a priori and used to increase the validity of our analysis. Limitations of this study are the relatively small sample size, the cross-sectional nature, and the need to adjust for age differences between the groups. A larger study with follow-up to provide a longitudinal or prospective component would be highly desirable to extend our present findings.

Briefly, we observed an interaction between testosterone and APOE {epsilon}4 on cognition in healthy older men. In men not possessing an {epsilon}4 allele, higher testosterone concentrations were associated with better general cognition. However, higher testosterone concentrations in men who possessed an {epsilon}4 allele had lower performance on executive functioning, working memory, and attention tasks. APOE {epsilon}4 status should be taken into account when investigating the relationship between androgens and cognition in older men.


   Acknowledgments
 
We thank the team at the Moss Street Centre, the Department of Biochemistry, and the Specimen Reception Area at Fremantle Hospital for their technical assistance. In addition, we acknowledge staff of the Special Chemistry Section (Biochemistry Department, Royal Perth Hospital) for the hormone assays. We are also grateful to the participants of the Fremantle Endocrinology of Ageing Research Study for their involvement.


   Footnotes
 
First Published Online December 20, 2005

Abbreviations: AD, Alzheimer’s disease; APOE, apolipoprotein E; CAMCOG-R, Cambridge Cognitive Assessment-revised; D-KEFS, Delis and Kaplan Executive Function System; EFWMA, executive functioning, working memory, and attention; FSIQ, full-scale intelligence quotient; FT, free testosterone; MANCOVA, multivariate analysis of covariance; VR, visual reproduction; WMS-III, Wechsler Memory Scale-Third Edition.

This work was supported by a Clinical Investigator Award (to B.B.Y.) from the Sylvia and Charles Viertel Charitable Foundation, New South Wales, Australia, and research grants from the Hollywood Private Hospital Research Foundation and the South Metropolitan Area Health Service Human Research Ethics Committee (to R.M.C. and B.B.Y.). R.M.C., J.K.F., and R.N.M. were supported by the McCusker Foundation for Alzheimer’s Disease Research.

The authors have no conflict of interest.

Received May 13, 2005.

Accepted December 8, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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