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Neurobiology of Aging 32 (2011) 1615–1625

Salivary cortisol, APOE-�4 allele and cognitive decline in a prospectivestudy of older persons

Lotte Gerritsen a, Hannie C. Comijs b,∗, Dorly J.H. Deeg b,Brenda W.J.H. Penninx b, Mirjam I. Geerlings a

a University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, The Netherlandsb VU University Medical Center, Department of Psychiatry, EMGO Institute, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands

Received 7 April 2009; received in revised form 7 September 2009; accepted 27 September 2009Available online 30 October 2009

bstract

bjective: We determined whether salivary cortisol levels were associated with cognitive decline at follow-up in older persons and whetherhis association was modified by the APOE-�4 allele.

ethods: Within the Longitudinal Aging Study Amsterdam (LASA), a population-based prospective cohort study, 911 persons (74.5 ± 7.2ears, 46.4% male) collected salivary cortisol in the morning and late in the evening. At baseline and after 4 years of follow-up, global cognitiveunctioning, verbal memory performance, and processing speed were assessed. The longitudinal associations between cortisol measures andognitive decline were estimated using linear mixed models, adjusted for potential confounders and the modifying role of the APOE-�4 alleleas examined.esults: Lower morning cortisol levels, higher evening cortisol levels, and flattened diurnal variability of cortisol levels were associated with

ncreased risk for memory decline in APOE-�4 carriers but not in non-carriers.

onclusion: Our findings suggest that in this older non-demented population APOE-�4 carriers may be more vulnerable to the potentialetrimental effect of hypothalamic-pituitary-adrenal axis dysfunction on verbal memory performance.

2009 Elsevier Inc. All rights reserved.

eywords: Cortisol; HPA axis; Cognitive decline; Apolipoprotein E; Aging

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. Introduction

It has frequently been hypothesized that chronic exposureo glucocorticoids has a damaging effect on the brain andognitive functioning (Lupien et al., 2007; Sapolsky, 2003).iological evidence supporting this hypothesis suggests that

ncreased levels of glucocorticoids are associated with neu-odegeneration of the hippocampus (De Kloet, 2004). Inumans, increased levels of glucocorticoids and reducedlucocorticoid feedback inhibition of the hypothalamic-ituitary-adrenal (HPA) axis have been associated with

ging (Kudielka et al., 2004; Wilkinson et al., 2001). Also,europsychiatric disorders associated with HPA axis dys-unction, such as depressive disorder, posttraumatic stress

∗ Corresponding author. Tel.: +31 20 4449327.E-mail address: h.comijs@vumc.nl (H.C. Comijs).

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197-4580/$ – see front matter © 2009 Elsevier Inc. All rights reserved.oi:10.1016/j.neurobiolaging.2009.09.007

isorder and Alzheimer’s disease have been found to bessociated with smaller hippocampal volumes (Geuze et al.,005; Gosche et al., 2002). Based on these findings it haseen hypothesized that high levels of cortisol contribute toippocampal atrophy, cognitive decline and increased riskor Alzheimer’s disease (Lupien et al., 1999; O’Brien et al.,004).

Prospective studies on the relation between cortisol lev-ls and cognitive decline have demonstrated highly variableesults. Some studies found that high levels of cortisol at base-ine (Karlamangla et al., 2005; Li et al., 2006) or increase inortisol levels over time (Lupien et al., 1994; Seeman et al.,997) were associated with memory decline or decline inlobal cognitive functioning. However, other studies did not

nd that cortisol levels were associated with cognitive declineCarlson and Sherwin, 1999; Kalmijn et al., 1998; Kuningast al., 2007).

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616 L. Gerritsen et al. / Neurobio

Contrary to HPA axis regulation, the apolipoprotein EAPOE)*�4 allele is a well established risk factor for cog-itive decline and Alzheimer’s disease (Raber et al., 2004;mall et al., 2004). APOE is a glycoprotein, which is involved

n the transport of cholesterol and other lipids through cellembranes and in the brain it is thought to play a role in

ell growth and neuronal regeneration. It has been demon-trated that the APOE-�4 allele is associated with higherevels of cortisol in CSF in patients with Alzheimer’s dis-ase (Peskind et al., 2001). Also, two recent cross-sectionaltudies investigated the modifying effect of APOE-�4 on thessociation between cortisol levels and cognitive function-ng. One of these reported that elevated cortisol levels weressociated with poorer cognitive functioning in older personsith two APOE-�4 alleles but not in heterozygotes or non-

arriers (Lee et al., 2008), while the other study did not findhat APOE-�4 modified this association (Fiocco et al., 2008).hese results are highly interesting and it would be of great

mportance to investigate longitudinally whether the APOE-4 allele modifies the association between cortisol levels andognitive decline.

Therefore, in the present study, we examined firstlyhether salivary cortisol levels, collected in the morning and

ate in the evening, were associated with decline in global cog-itive functioning, information processing speed and verbalemory performance in a large population-based cohort of

lder people with 4 years of follow-up. Secondly, we exam-ned whether this association was modified by the APOE-�4llele. We hypothesized that higher levels of cortisol woulde associated with cognitive decline in APOE-�4 carriers, butot in non-carriers.

. Methods

.1. LASA

Data were used from the Longitudinal Aging Study Ams-erdam (LASA). LASA is a population-based prospectiveohort study among 3107 persons initially aged 55–85 yearsn the Netherlands that started in 1992/1993 (T1). Details ofhis cohort study have been described previously (Deeg et al.,002). For this study, data were used from the third follow-upT4) in 2001–2002 when 1691 subjects participated (81% of3) and the fourth follow-up (T5) in 2005–2006 when 1266ubjects participated (74% of T4). Of the 1416 participantsho were lost to follow-up between T1 and T4 1050 (33.8%f the T1 sample) had died, 112 (3.6%) indicated by self-eport or proxy that they were too ill or cognitively impairedo be interviewed, 222 (7.1%) indicated that they were noonger interested in participating in the study, and 32 (1.0%)ould not be contacted.

.2. Cortisol measurement

Saliva samples were collected with the “Salivette” devicerom Sarstedt, in Nümbrecht, Germany. Materials for saliva

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Aging 32 (2011) 1615–1625

ampling and detailed instructions were sent home to the par-icipants. Participants had to collect saliva within 30 min afterwakening and just before going to bed. In order to preventontamination with blood, participants were asked not to eatr brush their teeth and had to rinse their mouth and wait 10in before starting to chew the cotton ball (Schoorlemmer

t al., 2009). The samples were kept in the refrigerator untilollected by the interviewer the next day.

In the laboratory, the saliva samples were centrifuged andtored at −20 ◦C until analysis.

Cortisol levels (nmol/L) were determined using radiommunoassay coated tubes (Spectria Orion Diagnostics, Fin-and). The detection limit was 1.5 nmol/L. The intra-assayoefficient of variation was 7% for cortisol levels around0 nmol/L and 19% for cortisol levels around 1.3 nmol/L,hereas corresponding inter-assay coefficients of variationere 5% and 19% (Peeters et al., 2008).

.3. Cognition

Global cognitive functioning was determined using theini Mental State Examination (MMSE) (Folstein et al.,

975). Because MMSE scores had a skewed distribution, weomputed the MMSE score into a reverse score and appliedatural log transformation: ln(31-MMSE score) (van denommer et al., 2008), to obtain a normal distribution.

Verbal memory performance was tested with the 15-wordearning test (Brand and Jolles, 1985; Comijs et al., 2004), inhich 15 unrelated words had to be learned over three con-

ecutive trials. After each trial participants had to recall asany words as possible (immediate recall). After a distrac-

ion period of 20 min, participants were asked to recall theords they had learned during the three trials. The retention

core was calculated by dividing the delayed recall score byhe maximum number of words recalled during the immediateecall.

Information processing speed was tested using an adjustedersion of the digit-coding task (Savage, 1984). In this taskwo rows of characters were shown. Each character in the firstow belongs to a character in the second row. Participants hado complete as many character combinations as possible byerbally naming the corresponding character. This test wasepeated over three trials of one minute each. The trial inhich the respondent gave the most answers was included as

he maximum score.

.4. APOE genotype determination

Serum samples collected at T2 and T3 were frozen at80 ◦C until APOE genotypes were determined by isoelec-

mmunoblotting. Participants were classified as APOE-�4arriers for those with an APOE-�4 isoform (genotypes �2/4,3/4, �4/4) and as non-carriers for those without an APOE-�4soform (genotypes �2/2, �2/3, �3/3) (Dik et al., 2001).

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L. Gerritsen et al. / Neurobio

.5. Other variables

Age, gender and level of education were recorded dur-ng the baseline interview of LASA (T1). Educational levelas recorded in seven categories ranging from 6 years of

ducation or less to college or university education. At T4lcohol consumption, smoking habits, hours of sleep, historyf diabetes, atherosclerosis, heart disease, and stroke weressessed with self-report questionnaires. Alcohol consump-ion was expressed as number of drinks per week and wasategorized in three groups (no alcohol use; on average <14rinks weekly; ≥14 drinks weekly). Smoking habits were cat-gorized in current and non-current smoker. Medication useas assessed by self-report and inspection of the medicine

ontainers (Kriegsman et al., 1996). Blood pressure was mea-ured twice, and the average of the two measurements wasalculated. Hypertension was defined as a diastolic tension90 mmHg or a systolic tension above 140 mmHg or use ofnti-hypertensive medication. Body Mass Index (BMI) wasalculated from measured weight and height and expressed asg/m2. Depressive symptoms were measured using the Dutchersion of the Center for Epidemiologic Studies Depressioncale (CES-D) (Beekman et al., 1997).

.6. Study sample

Of the 1691 persons participating at T4, saliva was col-ected by 1184 participants, of whom 1010 persons hadata on APOE genotype. From these, 27 participants (2.7%)sed corticosteroids and were excluded from the study sam-le. Participants with possible dementia (N = 23) were alsoxcluded from the study sample. Possible dementia wasefined as a persistent decline in MMSE score of more thanstandard deviations from the mean over three consecutiveeasurements and by indication of a proxy (van den Kommer

t al., 2008). Of the saliva samples, 21 morning samples and7 evening samples were excluded because of insufficientolume of saliva or improbable cortisol levels (cortisol levelsigher than 4 standard deviations above mean morning corti-ol) (Peeters et al., 2008). Missing data on covariates existedor 32 participants, leaving 911 participants for data-analysis.f these, complete data was available for 698 participants for

ollow-up measurements 4 years later.

.7. Data analysis

First, baseline characteristics were calculated according toertiles of diurnal variability levels, calculated as the absoluteifference between morning and evening levels. Differencesn baseline characteristics were analyzed using t-tests for nor-

ally distributed data and Chi-square and Mann–Whitneyests for non-normally distributed data.

Second, the longitudinal association between salivary cor-isol and cognitive decline was estimated using randomoefficient analyses, in which the rate of change in cognitiveunctioning over time (i.e. intercepts and slopes) was fitted

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Aging 32 (2011) 1615–1625 1617

s random effects. This method takes into account multiplebservations per subject that are likely to be correlated. Theifferent cognition measures were entered as dependent vari-bles and the cortisol measures were entered as independentariables per standard deviation increase. The main effects ofortisol and age (as the time variable) were entered as contin-ous variables. Age was centered around the mean age of thetudy population at baseline (75.5 years), to obtain interceptshat represented the mean score on the respective cognitiveest. To estimate the rate of change in cognition over timeage) as a function of cortisol levels interaction terms betweenortisol and age were entered in the same model. Analysesere adjusted for sex, level of education, diabetes, atheroscle-

osis, heart disease, stroke, hypertension, BMI, mean hours ofleep, smoking and alcohol habits, APOE-�4 (one or two �4lleles vs. non-carriers) and depressive symptoms. The mod-ls with diurnal variability as the dependent variable werelso adjusted for morning levels of cortisol, to obtain relativeiurnal measures.

Third, to examine whether APOE-�4 modified the asso-iation between cortisol and cognitive decline we enterednteraction terms between cortisol measures, APOE-�4 andime to the fully adjusted models, including the interactionerms nested within this interaction. Finally, we repeated allnalyses after excluding APOE-�2 carriers (N = 113).

All analyses were carried out in Statistical Analysis Sys-em (SAS), version 9.1 (Cary, NC, USA).

. Results

Table 1 presents the characteristics of the study sampleN = 911), for which complete data was available, and the80 subjects who were excluded because of non-response andncomplete data. Compared with those who were excluded,he participants in the study sample were significantlyounger, more often male, were less often current smokers,ad less often CVA, diabetes and an APOE-�4 allele andad better memory functioning and higher levels of morningortisol (p < 0.05).

Between baseline and our follow-up measurement 213articipants were lost to follow-up. Loss to follow-up wasssociated with significantly higher levels of evening corti-ol, but not with awakening cortisol, diurnal variability ofortisol or APOE-�4.

In our study sample the overall mean age was 75.5 ± 6.8ears, 47% was male, median morning and evening cor-isol levels were 15.0 (10–90%: 7.5–17.0) nmol/L and.9 (10–90%: 1.5–5.6) nmol/L respectively, and 25% werePOE-�4 carriers. Table 2 shows the baseline characteristicsf the study sample according to tertiles of diurnal variabil-ty of cortisol. Participants in the lowest tertile of diurnal

ariability were somewhat older, more often male, had moreften diabetes and cerebrovascular diseases and had lowercores on cognitive tests than participants in higher tertilesp < 0.05).

1618 L. Gerritsen et al. / Neurobiology of Aging 32 (2011) 1615–1625

Table 1Characteristics of the study sample and subjects excluded from the analysis because of non-response or missing data.

Study sample Subjects excluded

N 911 780Mean age (SD) 75.5 (6.8) 77.6 (8.9)*

Male (%) 46.7 37.4*

Mean level of education (SD)a 3.7 (2.0) 3.4 (2.0)Mean body mass index (SD) 27.4 (4.2) 27.5 (4.3)Atherosclerosis (%) 10.1 12.2Heart disease (%) 29.8 29.2Cerebrovascular disease (%) 7.0 11.7*

Hypertension (%) 31.6 29.7Diabetes (%) 9.6 12.4*

Current smoker (%) 14.3 17.1*

Alcohol intakeNo alcohol use (%) 19.3 23.1<14 drinks per week (%) 59.5 55.4≥14 drinks per week (%) 21.5 21.2Median depression score (10–90%)b 7.0 (1.0–18.0) 7.0 (1.0–20.0)Median morning cortisol (10–90%) 15.0 (7.4–27.0) 14.0c,* (7.0–24.0)Median evening cortisol (10–90%) 2.9 (1.5–5.7) 2.9c (1.6–6.6)Median MMSE score (10–90%) 28.0 (25.0–30.0) 28.0 (23.0–30.0)Mean digit-coding test score (SD) 26.5 (7.2) 25.3 (7.8)Mean AVLT immediate recall (SD) 21.0 (6.3) 18.7 (7.2)*

Mean AVLT delayed recall (SD) 6.4 (3.0) 5.5 (3.3)*

Mean AVLT retention (SD) 70.6 (24.0) 63.4 (28.5)*

APOE-�4 carriers (%) 25.1 30.8d

a Educational level ranges from 0 (<6 years of education) to 9 (university).b Depression score measured with Center for Epidemiological Studies Depression Scale (0–30).c bjects i

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Table 3 presents the adjusted associations between cortisoleasures and cognition measures. Scores on all cogni-

ive tests declined over time, but salivary cortisol levelsere not associated with decline over time on any of these

ests, although significant main effects were observed forigher evening cortisol levels and flattened diurnal variabilityith poorer memory performance, suggesting that increased

vening levels at baseline was associated with poorer mem-ry performance at baseline as well as at follow-up but notith more decline in memory performance.When we tested interactions between cortisol mea-

ures, APOE-�4 and time, significant interactions wereound for morning cortisol*APOE-�4*time on immediateecall (B = 0.18; 95% CI 0.05 to 0.304, p < 0.01); diurnalariability*APOE-�4*time on immediate recall (B = 0.19;5% CI 0.07 to 0.31, p < 0.01); evening cortisol*APOE-4*time on delayed recall (B = 0.09; 95% CI 0.01 to 0.17,= 0.02); and diurnal variability*APOE-�4*time on delayed

ecall (B = 0.05; 95% CI 0.00 to 0.11, p = 0.08). Table 4resents the adjusted associations of cortisol measures withmmediate and delayed recall stratified for APOE-�4. In thePOE-�4 carriers, but not in non-carriers, lower morning cor-

isol and flattened diurnal variability were associated withore decline on immediate recall score. Also, in APOE-

4 carriers but not in non-carriers, higher evening cortisolnd flattened diurnal variability were associated with moreecline on delayed recall score. Figs. 1 and 2 present these

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esults of the random coefficient analyses with cortisol mea-ures categorized into tertiles, for immediate recall andelayed recall respectively. When we excluded the APOE-2 carriers from the sample the results did not materiallyhange (data not shown).

. Discussion

In this large community-based population of older per-ons, we observed that lower morning cortisol levels, highervening cortisol levels, and flattened diurnal variability ofortisol levels were associated with increased risk for mem-ry decline in APOE-�4 carriers but not in non-carriers.ortisol levels were not associated with decline in global cog-itive functioning or information processing speed, neither inPOE-�4 carriers nor in non-carriers.Strengths of this study are that we investigated the relation

etween cortisol and cognitive decline in a prospective designnd in a large and population-based cohort of older per-ons. Furthermore, we had data on several cognitive domains,hich made it possible to study not only memory functioningut global cognitive functioning and information process-

ng speed as well. Additionally, we were able to adjust theelations for a large number of potential confounders.

A limitation of our study is that we do not know exactly athich time the saliva samples were taken, as the participants

L. Gerritsen et al. / Neurobiology of Aging 32 (2011) 1615–1625 1619

Table 2Baseline characteristics of the study sample per tertile of diurnal variability of cortisol.

Tertiles of diurnal variability of cortisol

≤8.6 nmol/L 8.61–14.0 nmol/L ≥14.01 nmol/L p-Value*

N 323 283 305Mean age (SD) 76.0 (7.2) 75.7 (6.6) 74.7 (6.6) 0.09Male (%) 50.3 49.5 41.0 0.02Mean level of education (SD)a 3.7 (2.0) 3.8 (2.0) 3.7 (2.0) 0.85Mean body mass index (SD) 27.9 (4.1) 27.2 (4.2) 27.2 (4.4) 0.10Atherosclerosis (%) 9.3 10.2 9.9 0.86Heart disease (%) 30.5 29.3 27.9 0.81Cerebrovascular disease (%) 9.6 6.4 4.8 0.06Hypertension (%) 29.4 31.8 32.4 0.44Diabetes (%) 13.6 7.1 8.0 0.02Current smoker (%) 15.6 13.8 12.2 0.57

Alcohol intakeNo alcohol use (%) 20.9 18.0 19.2 0.64<14 drinks per week (%) 56.6 62.9 58.7 0.25≥14 drinks per week (%) 22.5 19.1 22.1 0.51Median depression score (10–90%)b 8.0 (1.0–19.0) 7.0 (1.0–17.6) 7.0 (1.0–17.7) 0.37Median morning cortisol (10–90%) 9.0 (5.6–13.0) 14.0 (11.0–17.0) 22.0 (17.0–33.0) 0.00Median evening cortisol (10–90%) 3.1 (1.6–6.9) 2.7 (1.5–5.0) 2.8 (1.5–5.2) 0.00Median MMSE score (10–90%) 27.5 (24.0–30.0) 28.0 (25.0–30.0) 28.0 (25.0–30.0) 0.08Mean digit-coding test score (SD) 26.1 (7.2) 26.9 (7.0) 27.4 (7.0) 0.04Mean AVLT immediate recall (SD) 20.0 (6.3) 21.0 (6.3) 22.1 (6.1) 0.00Mean AVLT delayed recall (SD) 6.1 (3.0) 6.4 (3.0) 6.9 (3.0) 0.00Mean AVLT retention (SD) 70.2 (24.1) 70.4 (23.8) 73.2 (22.3) 0.22APOE-�4 carriers (%) 25.4 25.4 24.6 0.98

a Educational level ranges from 0 (≤6 years of education) to 9 (university).pressionn–Whi

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ere asked to collect saliva within 30 min after awakeningnstead of directly at awakening or 15 or 30 min after awak-ning. Cortisol follows a specific circadian rhythm, with peakevels 30 min after awakening and a nadir at night. Conse-uently, it is unclear whether the morning samples in ourtudy reflect the awakening level, the peak at 30 min afterwakening, or any time within this 30 min interval. Althoughhis will have lead to misclassification, we find it unlikely thatt was systematic, i.e. that participants who showed cognitiveecline during follow-up selectively collected saliva either atwakening or 30 min after awakening. Rather, we think thisas lead to random misclassification, which will have leado dilution of estimates. Additionally, it is recommended toollect cortisol samples on two consecutive days (Kraemer etl., 2006), because cortisol levels are rather variable withinndividuals. However, our large sample size may have largelyompensated for the possible variability in cortisol measures.

Two previous recent studies also examined the rela-ion between cortisol levels and cognitive performance inPOE-�4 carriers and non-carriers. One study found that

n APOE-�4 carriers, but not in non-carriers, cortisol levelsere associated with poorer cognitive functioning (Lee et

l., 2008), but in the second study no differences were foundetween APOE-�4 carriers and non-carriers (Fiocco et al.,

008). Although our findings are in line with the first study,oth studies differed from ours on several methodologicalspects. For instance, in the latter study 24 h serum cortisol

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n Scale (0–30).tney tests for non-normally distributed data.

as collected in a small sample (N = 17) (Fiocco et al., 2008),hile in the first study cortisol levels were measured during

ognitive testing, as a measure of stress (Lee et al., 2008).To our knowledge, this is the first study to examine the

odifying role of APOE-�4 in the relation between corti-ol levels and cognitive decline using a prospective design.he findings of increased risk for memory decline but notecline in global cognitive functioning or information pro-essing speed are consistent with a previous study, whicheported that APOE-�4 carriers predominantly show atrophyf brain structures which are related to memory performanceGeroldi et al., 1999). Results from animal studies show thatlucocorticoid receptors are distributed in brain structures,uch as the limbic system, hypothalamus and prefrontal cor-ex (Sanchez et al., 2000; Veldhuis et al., 1982). Therefore,

emory performance is more likely to be affected by cor-isol than cognitive functions that do not rely on specificrain structures, such as information processing speed andlobal cognitive functioning (Ikram et al., 2008). It is alsoossible, however, that we did not find an association withecline in global cognitive functioning because our studyample showed a relatively small decline on the MMSE mak-ng it more difficult to find a significant association. Also, the

MSE is a relatively insensitive measure of global cognitive

mpairment in non-demented elderly and it may have been

ore difficult to detect subtle changes in cognitive function-ng.

1620 L. Gerritsen et al. / Neurobiology of Aging 32 (2011) 1615–1625

Table 3Adjusted associations between cortisol measures and cognition scores for whole study sample.

Global cognitive functioninga Information processing speedb

B (95% CI) B (95% CI)

Morning cortisol (per 1 SD increasec) 0.02 (−0.02 to 0.05) 0.14 (−0.27 to 0.55)Intercept 28.97 (28.70 to 29.25) 26.61 (23.52 to 26.69)Time −0.03 (−0.04 to −0.02)* −0.36 (−0.46 to −0.26)*

Time*morning cortisold 0.00 (−0.01 to 0.00) −0.01 (−0.06 to 0.03)

Evening cortisol (per 1 SD increasee) 0.03 (0.00 to 0.06) −0.18 (−0.57 to 0.21)Intercept 29.01 (28.75 to 29.26) 27.24 (24.32 to 30.16)Time −0.03 (−0.03 to −0.02)* −0.38 (−0.44 to −0.32)*

Time*evening cortisold 0.00 (0.00 to 0.01) 0.01 (−0.05 to 0.04)

Diurnal variability (per 1 SD increasef) 0.01 (−0.07 to 0.10) 0.22 (−0.77 to 1.22)Intercept 28.97 (28.70 to 29.34) 26.80 (23.71 to 26.89)Time −0.03 (−0.04 to −0.02)* −0.39 (−0.48 to 0.30)*

Time*diurnal variabilityd 0.00 (−0.01 to 0.00) 0.00 (−0.04 to 0.05)

Verbal memoryg – immediate recall Verbal memoryg – delayed recall Verbal memoryg – memory retention

B (95% CI) B (95% CI) B (95% CI)

Morning cortisol (per 1 SD increasec) 0.18 (−0.02 to 0.05) 0.02 (−0.16 to 0.19) −0.72 (−2.07 to 0.63)Intercept 23.06 (20.30 to 25.83) 7.57 (6.20 to 8.93) 79.89 (69.19 to 90.59)Time −0.37 (−0.47 to −0.26)* −0.17 (−0.22 to −0.11)* −0.93 (−1.40 to −0.47)*

Time*morning cortisold −0.01 (−0.06 to 0.04) 0.00 (−0.04 to 0.02) 0.05 (−0.16 to 0.25)

Evening cortisol (per 1 SD increasee) −0.20 (−0.55 to 0.13) −0.20 (−0.37 to −0.03)* −1.55 (−2.81 to −0.28)*

Intercept 23.83 (21.22 to 26.43) 7.81 (6.52 to 9.08) 79.23 (69.09 to 89.36)Time −0.37 (−0.43 to −0.31)* −0.16 (−0.20 to −0.13)* −0.70 (−0.97 to −0.42)*

Time*evening cortisold 0.00 (−0.04 to 0.05) 0.00 (−0.02 to 0.02) −0.16 (−0.36 to 0.05)

Diurnal variability (per 1 SD increasef) 0.73 (−0.17 to 1.64) 0.54 (0.11 to 0.99)* 4.15 (0.44 to 7.87)*

Intercept 23.20 (20.44 to 25.96) 7.69 (6.33 to 9.05) 80.70 (70.02 to 91.39)Time −0.39 (−0.48 to −0.27)* −0.18 (−0.22 to −0.14)* −1.06 (−1.46 to −0.66)*

Time*diurnal variabilityd 0.01 (−0.03 to 0.06) 0.01 (−0.01 to 0.03) 0.15 (−0.05 to 0.36)

Associations are adjusted for sex, levels of eductaion, atherosclerosis, heart disease, cerebrovascular diseases, hypertension, diabetes, BMI, smoking anddrinking habits, APOE-�4 and depressive symptoms.

a As measured with Mini Mental State Examination.b As measured with Digit-coding test.c SD morning cortisol: 8.07 nmol/L.d Time is represented by mean age at baseline; the interaction term reflects the rate of cognitive decline over time.e SD evening cortisol: 4.36 nmol/L.f SD diurnal variability: 7.47 nmol/L.

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g As measured with 15-word learning test.* p < 0.05.

In our study frontal lobe functions, like executive function-ng, were not measured, whereas it has been suggested thatarticularly frontal lobe functions are sensitive to the effectsf glucocorticoids (Lupien et al., 2007) and aging (Traykov etl., 2007). So it remains unresolved to which extent cortisolevels are associated with executive functioning in APOE-�4arriers.

We observed that higher levels of evening cortisol weressociated with more rapid decline on delayed recall, andhat lower levels of morning cortisol were associated with

ore rapid decline on immediate recall. Delayed recall issually considered to be a hippocampal dependent memory

unction (Kramer et al., 2005), whereas immediate recall alsoelies on cognitive functions such as attention (Buckner et al.,000), which are not located in specific brain areas. Miner-

Dra

locorticoid receptors (type I) are mainly distributed in theippocampus, whereas the glucocorticoid (type II) receptorsre also distributed in other areas of the brain, such as therefrontal cortex (Sanchez et al., 2000). These two receptorypes not only differ in location of distribution, but also ininding affinity. Type I receptors bind glucocorticoids withn affinity which is 6–10 times higher than that of type IIeceptors. As a consequence, type I receptors are occupiedhen glucocorticoid levels are low to moderate, for instance

n the evening, whereas type II receptors are only occupiedhen glucocorticoid levels are higher, as is usually the case

n the morning and during stressful circumstances (Reul and

e Kloet, 1985). Since the hippocampus plays an inhibitive

ole in HPA axis regulation (Jacobson and Sapolsky, 1991)nd type I receptors are mainly distributed in the limbic sys-

L. Gerritsen et al. / Neurobiology of Aging 32 (2011) 1615–1625 1621

Table 4Adjusted associations between cortisol measures and verbal memory scores, stratified for APOE-�4 carriers and non-carriers.

Verbal memory – immediate recalla Verbal memory – delayed recalla

APOE-�4 carriers APOE-�4 non-carriers APOE-�4 carriers APOE-�4 non-carriers

B (95% CI) B (95% CI) B (95% CI) B (95% CI)

Morning cortisol(per 1 SD increaseb) −0.13 (−0.90 to 0.63) 0.29 (0.12 to 0.71)* −0.17 (−0.54 to 0.21) 0.08 (−0.13 to 0.28)Intercept 26.67 (20.70–32.64) 21.61 (18.46–24.72) 9.96 (7.03–12.90) 6.68 (5.14–8.22)Time −0.69 (−0.94 to −0.44)* −0.29 (−0.41 to −0.17)* −0.28 (−0.41 to −0.16)* −0.13 (−0.19 to −0.08)*

Time*morning cortisolc 0.14 (0.02–0.25)* −0.04 (−0.09 to 0.01) 0.04 (−0.01 to 0.10) −0.01 (−0.04 to 0.01)

Evening cortisol(per 1 SD increased) 0.03 (−0.98 to 1.05) −0.22 (−0.60 to 0.15) 0.21 (−0.29 to 0.71) −0.21 (−0.40 to −0.02)*

Intercept 26.43 (20.88–31.98) 22.69 (19.73–25.64) 9.29 (6.54–12.04) 7.12 (5.67–8.57)Time −0.43 (−0.60 to −0.26)* −0.36 (−0.43 to −0.28)* −0.26 (−0.35 to −0.18)* −0.15 (−0.18 to −0.12)*

Time*evening cortisolc 0.04 (−0.13 to 0.21) 0.00 (−0.04 to 0.05) 0.09 (0.01–0.17)* −0.01 (−0.03 to 0.01)

Diurnal variability(per 1 SD increasee) 1.40 (−1.95 to 4.75) 0.68 (−0.28 to 1.64) 0.40 (−1.26 to 2.07) 0.57 (0.10–1.03)*

Intercept 26.32 (20.31–32.32) 21.92 (18.81–25.03) 9.95 (6.96–12.93) 6.88 (5.35–8.40)Time −0.68 (−0.90 to −0.47)* −0.32 (−0.43 to −0.22)* −0.28 (−0.39 to −0.17)* −0.15 (−0.20 to −0.11)*

Time*diurnal variabilityc 0.17 (0.06–0.30)* −0.02 (−0.07 to 0.03) 0.05 (−0.01 to 0.11)* 0.00 (−0.03 to 0.02)

Associations are adjusted for sex, levels of educations, atherosclerosis, heart disease, cerebrovascular diseases, hypertension, diabetes, BMI, smoking anddrinking habits and depressive symptoms.

a As measured with 15-word learning test.b SD morning cortisol: 8.07 nmol/L.c Time is represented by mean age at baseline; the interaction term reflects the rate of cognitive decline over time.

tch

iitratcelaaeertot1

mwitrM

crsbi1vpI2iocotcarcsu2

lti

d SD evening cortisol: 4.36 nmol/L.e SD diurnal variability: 7.47 nmol/L.* p < 0.05.

em, it is possible that the association between high eveningortisol levels and decline on delayed recall is a result of earlyippocampal atrophy (Sapolsky et al., 1986).

Our finding of lower morning cortisol and more decline onmmediate recall is more difficult to explain since the major-ty of studies reported poorer memory functioning in relationo higher cortisol levels. Although, so far no previous studyeported (Li et al., 2006) or found (Kuningas et al., 2007)n association between memory decline and morning cor-isol, but only with evening cortisol (Li et al., 2006), 24 hortisol (Seeman et al., 1997) and with cortisol responses toxperimental stress (Lee et al., 2007). Lower morning cortisolevels have however been found in patients with hippocampaltrophy (Buchanan et al., 2004) and in patients with severemnesia and possible medial temporal lobe atrophy (Wolft al., 2005). Furthermore, it is also possible that not onlylevated cortisol levels, but also lower levels may increaseisk for memory decline. This is in line with the hypothesishat memory performance is optimal during moderate levelsf glucocorticoids (De Kloet et al., 1999) when the ratio ofype I/type II receptor occupation is highest (Diamond et al.,992).

Although our findings of higher evening cortisol withore decline on delayed recall and lower morning cortisolith more decline on immediate recall may seem discrepant;

t should be noted that the direction of the associations was

he same for lower morning levels of cortisol with delayedecall and for higher evening levels and immediate recall.

oreover, flattened diurnal variability was significantly asso-

nHd

iated with more rapid decline on both immediate and delayedecall. It is thus possible that the diurnal variability of corti-ol is of importance, rather than morning or evening levelsy itself. It has been suggested that the diurnal variabilitys a good marker for HPA axis functioning (Smyth et al.,997; Stone et al., 2001) and that flattening of the diurnalariability is associated with aging, frailty, memory com-laints and several somatic diseases (Fiocco et al., 2006;ce et al., 2004; Lasikiewicz et al., 2008; Rosmond et al.,003; Stone et al., 2001; Varadhan et al., 2008). Our find-ng that cortisol levels increased risk for memory declinenly in APOE-�4 carriers could also suggest that APOE-�4arriers are more vulnerable to potential detrimental effectsf dysfunction of the HPA axis on the hippocampus. Also,he modifying role of APOE-�4 may suggest that glucocorti-oids do not play a direct causal role in hippocampal atrophynd memory decline, but that a subgroup of APOE-�4 car-iers have an early stage of Alzheimer’s disease althoughlinical symptoms are not yet present. If true, this woulduggest that our findings may be explained by a sharednderlying early Alzheimer’s disease process (Swaab et al.,005).

In conclusion, in this older non-demented populationower morning cortisol levels, higher evening levels and flat-ened diurnal variability of cortisol were associated withncreased risk of memory decline in APOE-�4 carriers butot in non-carriers. Future studies should determine whetherPA axis dysfunction in APOE-�4 carriers plays a role in the

evelopment of Alzheimer’s disease.

1622 L. Gerritsen et al. / Neurobiology of Aging 32 (2011) 1615–1625

F diurnaa lity of c

C

m

D

cot

A

Wlnih

ig. 1. Adjusted immediate recall scores per tertiles of morning cortisol andnd B: morning cortisol; C and D: evening cortisol; E and F: diurnal variabi

ontributors

All authors contributed to and have approved the finalanuscript.

isclosure statement

All authors have no conflict of interest regarding any finan-

ial, personal or other relationships with other people orrganizations within 3 years of beginning the work submittedhat could have inappropriately influenced their work.

art

l variability of cortisol, stratified for APOE*�4 carriers and non-carriers. Aortisol.

cknowledgements

The research is supported by the Dutch Ministry ofellfare and Health (VWS), a VIDI grant from the Nether-

ands Organization for Scientific Research (NWO: projecto. 917-66-311) and a grant from the Internationale Sticht-ng Alzheimer Onderzoek (ISAO). VWS, NWO and ISAOad no involvement in study design; in the collection,

nalysis and interpretation of data; in writing of theeport; and in the decision to submit paper for publica-ion.

L. Gerritsen et al. / Neurobiology of Aging 32 (2011) 1615–1625 1623

F rnal varB of corti

R

B

B

B

B

C

C

D

D

ig. 2. Adjusted delayed recall scores per tertiles of evening cortisol and diu: morning cortisol; C and D: evening cortisol; E and F: diurnal variability

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