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Increased CSF cortisol in AD is a function


of APOE genotype
E.R. Peskind, MD; C.W. Wilkinson, PhD; E.C. Petrie, MD; G.D. Schellenberg, PhD;
and M.A. Raskind, MD

Article abstract—Background: Increased hypothalamic–pituitary–adrenal (HPA) axis activity manifested by elevated


cortisol levels is observed in AD and may contribute to AD by lowering the threshold for neuronal degeneration. Presence
of the APOE-⑀4 allele increases risk for AD. Increased cortisol concentrations in apoE-deficient mice suggest that APOE
genotype may influence cortisol concentrations in AD. Methods: The authors measured cortisol levels in CSF and
determined APOE genotypes for 64 subjects with AD and 34 nondemented older control subjects. Results: CSF cortisol was
significantly higher in AD than in control subjects. CSF cortisol concentrations differed with respect to APOE genotype in
both subjects with AD (⑀4/⑀4 ⬎ ⑀3/4⑀ ⬎ ⑀3/⑀3) and normal older control subjects (⑀3/⑀4 ⬎ ⑀3/⑀3 ⬎ ⑀2/⑀3). Comparison of CSF
cortisol concentrations within the ⑀3/⑀4 and ⑀3/⑀3 genotypes revealed no differences between AD and control subject
groups. Conclusions: Higher CSF cortisol concentrations were associated with increased frequency of the APOE-⑀4 allele
and decreased frequency of the APOE-⑀2 allele in AD subjects relative to control subjects. This effect of APOE genotype on
HPA axis activity may be related to the increased risk for AD in persons carrying the APOE-⑀4 allele and decreased risk
for AD in persons carrying the APOE-⑀2 allele.
NEUROLOGY 2001;56:1094 –1098

Hypothalamic–pituitary–adrenal (HPA) axis activity cause glucocorticoid administration or stress-induced


is increased in AD, as manifested by increased con- glucocorticoid elevations in rats and tree shrews pro-
centrations of cortisol in plasma and urine and an duce hippocampal dendritic atrophy and neuronal
increased plasma cortisol response to stress.1-8 Be- loss,9-11 increased cortisol level in AD may lower the

From the Mental Illness Research, Education, and Clinical Center (MIRECC) (Drs. Peskind and Raskind) and Geriatric Research, Education, and Clinical
Center (GRECC) (Drs. Wilkinson and Schellenberg), VA Puget Sound Health Care System; and Departments of Psychiatry and Behavioral Sciences (Drs.
Peskind, Wilkinson, Petrie, and Raskind) and Medicine (Dr. Schellenberg), University of Washington School of Medicine, Seattle.
Supported by the Department of Veterans Affairs, National Institute on Aging (NIA AGO5136 and AGO8419), and the Joan Alhadeff Research Foundation.
Received August 14, 2000. Accepted in final form January 6, 2001.
Address correspondence and reprint requests to Dr. E.R. Peskind, Mental Illness Research, Education, and Clinical Center (116MIRECC), VA Puget Sound
Health Care System, 1660 S. Columbian Way, Seattle, WA 98108; e-mail: peskind.elaine@seattle.va.gov

1094 Copyright © 2001 by AAN Enterprises, Inc.


threshold for neuronal degeneration in this disor-
der.12 The mechanism responsible for increased HPA
axis activity in AD is unknown. Transgenic mice
lacking a functional APOE gene (APOE-⫺/⫺) have
aging-related increases in both basal plasma cortico-
sterone concentrations and an enhanced plasma cor-
ticosterone response to stress.13 In humans, APOE
genotype influences risk for developing AD: The ⑀4
allele increases risk,14 and the ⑀2 allele decreases
risk.15 Because apoE influences corticosteroid levels
in the mouse, the increased frequency of the
APOE-⑀4 genotype in AD could contribute to in-
creased glucocorticoid concentrations similar to those
found in APOE knockout mice.
Substantially increased cortisol concentrations in
AD have been demonstrated in CSF samples ob-
tained post mortem.16 Effects of AD on CSF cortisol
concentrations obtained ante mortem have not been
reported. Cortisol in CSF is a measure more relevant
to CNS effects of cortisol than cortisol in plasma17-19
and provides an approximation of the cortisol con-
Figure 1. CSF cortisol concentrations by APOE genotype
centration to which brain neurons are exposed. Here
in 64 patients with AD (open circles) and 34 nondemented
we asked whether CSF cortisol concentrations are ele-
older control subjects (filled circles). There was a signifi-
vated in AD ante mortem and, if so, whether APOE cant effect of the APOE-⑀4 allele on CSF cortisol concen-
genotype influences CSF cortisol concentrations. tration in AD subjects (APOE-⑀4/⑀4 ⬎ ⑀3/⑀4⬎ ⑀3/⑀3;
F[2,60] ⫽ 4.36, p ⬍ 0.02, all post hoc pairwise compari-
Methods. Subjects. This study was approved by the sons by Fisher’s protected least significant difference test,
Human Subjects Committee of the University of Washing- p ⬍ 0.05). There was a trend toward a stepwise effect of
ton. Subjects included 64 persons with AD (44 men and 20 APOE genotype on CSF cortisol level in control subjects
women; age ⫽ 67 ⫾ 1 years [mean ⫾ SEM; range 35 to 85 (APOE-⑀3/⑀4 ⬎ ⑀3/⑀3 ⬎ ⑀2/⑀3; F[2,30] ⫽ 3.31, p ⫽ 0.05).
years]) and 34 cognitively normal healthy older community
volunteers (22 men and 12 women; age ⫽ 71 ⫾ 1 years
[range 61 to 86 years]). Subjects were nonsmokers in good frozen immediately on dry ice and stored at ⫺70 °C until
general health and had been free of medications (except assay.
occasional nonprescription analgesics or laxatives) for at Cortisol radioimmunoassay. CSF cortisol was assayed
least 1 month before lumbar puncture. All were normoten- by radioimmunoassay with 125I kits from Pantex (Santa
sive at screening examination (⬍150/90 mm Hg) and Monica, CA) using a modification of the commercial proto-
within 25% of ideal body weight (Metropolitan Life Insur- col to increase sensitivity. The detection limit of this assay
ance tables, 1983). All subjects were free of past or present is 1 ng/mL (100 pg using a 0.1-mL sample). Intra- and
major psychiatric or neurologic disorders (other than AD), interassay coefficients of variation are 3.3 and 7.2%,
renal or hepatic disease, diabetes mellitus, and symptom- respectively.
atic cardiac disease. All subjects with AD met clinical diag- DNA allele typing for APOE. APOE genotypes were
nostic criteria for probable AD of the National Institute of determined using previously described PCR conditions23
Neurological and Communicative Disorders and Stroke20 and the HhaI restriction digest method.24
and Diagnostic and Statistical Manual of Mental Disorders Statistical analysis. Variables are expressed as means
(3rd edition, revised) criteria for dementia of the Alzhei- ⫾ SEM. Differences in age and CSF cortisol concentration
mer type. The mean Mini-Mental State Examination between the AD and normal control groups, both overall
(MMSE)21 score of the patients with AD was 16 ⫾ 1. The and within genotype, were compared by Student’s t-test
mean Clinical Dementia Rating (CDR)22 scale score of the (unpaired, two tailed). Differences in CSF cortisol concen-
patients with AD was 2.8 ⫾ 0.1. All subjects with AD were trations among APOE genotypes both within AD and con-
cooperative with the experimental procedure and free of trol groups and the combined AD plus control group were
disruptive agitation on the morning of the study. Normal evaluated by one-way analysis of co-variance (ANCOVA)
older subjects had MMSE scores between 26 and 30, no his- using age as the co-variate. Post hoc Fisher’s protected
tory or evidence of cognitive decline, and CDR scores of 0. least significant difference (PLSD) tests were used to eval-
CSF collection. Lumbar punctures were performed at uate differences between specific genotypes after a signifi-
the VA Puget Sound Health Care System. Subjects were cant ANCOVA.
studied between 0900 and 1100 hours after fasting since
midnight. Patients were placed at bedrest for 90 minutes. Results. Age and genotype relationships. Subjects with
Lumbar puncture was performed atraumatically with a AD were younger than control subjects (t ⫽ 2.14, p ⬍ 0.05),
25G spinal needle while the patient was maintained in the reflecting the presence of seven very-early-onset familial
lateral decubitus position. CSF cortisol was measured in AD subjects in the AD group. Of the 64 subjects with AD
the 9th to 13th mL of CSF removed. CSF samples were included in the analysis, 13 had the APOE-⑀4/⑀4 genotype,
April (2 of 2) 2001 NEUROLOGY 56 1095
34 had the APOE-⑀3/⑀4 genotype, and 17 had the APOE-
⑀3/⑀3 genotype. Two AD subjects had the APOE-⑀2/⑀4 geno-
type and two had the APOE-⑀2/⑀3 genotype; because of the
very low number of AD subjects with the ⑀2/⑀3 and ⑀2/⑀4
genotypes, these four subjects were not included in the
analysis. Of the 34 normal control subjects, 11 had the
APOE-⑀3/⑀4 genotype, 17 had the APOE-⑀3/⑀3 genotype,
and 6 had the APOE-⑀2/⑀3 genotype; all control subjects
were included in the analysis. AD subjects with the APOE-
⑀3/⑀3 genotype were younger (59 ⫾ 2 years) than AD sub-
jects with either the APOE-⑀3/⑀4 (69 ⫾ 1 years) or the
APOE-⑀4/⑀4 (72 ⫾ 1 years) genotype (F[2,61] ⫽ 11.3, p ⬍
0.0001). Also, age at AD onset was lower in APOE-⑀3/⑀3
subjects (53 ⫾ 3 years) than in either APOE-⑀3/⑀4 (63 ⫾ 1
years) or APOE-⑀4/⑀4 (67 ⫾ 1 years) subjects (F[2,60] ⫽
10.62, p ⬍ 0.0001). These differences were a function of the
APOE-⑀3/⑀3 group having five of seven subjects with early-
onset familial AD carrying the presenilin-1 or presenilin-2
mutations. There was no relationship between age and
APOE genotype in the normal control subjects (F[2,31] ⫽
0.56, p ⫽ 0.6). There was no relationship between APOE Figure 2. CSF cortisol concentrations by APOE genotype
genotype and duration of AD or MMSE score. in 64 patients with AD and 34 nondemented older control
CSF cortisol and genotype relationships. CSF cortisol subjects combined. CSF cortisol concentrations differ sig-
concentration was higher in the AD group than the normal nificantly by genotype: APOE-⑀4/⑀4 ⬎ ⑀3/⑀4 ⬎ ⑀3/⑀3 ⬎
older control group (0.82 ⫾ 0.03 versus 0.73 ⫾ 0.03 ng/mL; ⑀2/⑀3 (F[3,93] ⫽ 7.8, p ⫽ 0.0001). All post hoc pairwise
t ⫽ ⫺2.14, p ⬍ 0.05, unpaired, two tailed). Because CSF comparisons were at p ⬍ 0.05 (Fisher’s protected least sig-
cortisol level was positively correlated with age within nificant difference test) with the exception of APOE-⑀3/⑀3
both AD (r ⫽ 0.36, p ⬍ 0.01) and control (r ⫽ 0.51, p ⬍ versus APOE-⑀2/⑀3.
0.01) groups, ANCOVA for CSF cortisol level by APOE
genotype was performed with age as a co-variate. Within
subjects with AD, there was a dose effect of the APOE-⑀4 was a trend toward an inverse correlation between CSF
allele on CSF cortisol concentration (F[2,60] ⫽ 4.36, p ⬍ cortisol and MMSE scores within the cognitively normal
0.02) such that APOE-⑀4/⑀4 homozygotes had higher CSF older subjects (r ⫽ ⫺0.327, p ⫽ 0.06). There were no differ-
cortisol level than APOE-⑀3/⑀4 heterozygotes, who in turn ences in CSF cortisol concentration by CDR score among
had higher CSF cortisol level than APOE-⑀3/⑀3 homozy- AD subjects (F[4,55] ⫽ 1.82, p ⫽ 0.14).
gotes (all post hoc pairwise comparisons by Fisher’s PLSD
test, p ⬍ 0.05) (see figure 1). There was also a trend to- Discussion. These results demonstrate an effect of
ward a stepwise effect of APOE genotype on CSF cortisol APOE genotype on CSF cortisol concentrations in
in control subjects, such that APOE-⑀3/⑀4 ⬎ ⑀3/⑀3 ⬎ ⑀2/⑀3 older persons similar to the effect of APOE genotype
(F[2,30] ⫽ 3.31, p ⫽ 0.05) (see figure 1). Because compari- on the risk for expressing AD in later life.14,15 Sub-
son of CSF cortisol concentrations between AD and control jects with the APOE-⑀4 allele, which increases risk
subject groups within the APOE-⑀3/⑀4 and APOE-⑀3/⑀3 ge- for AD in a dose-dependent manner,14,25 had a dose-
notypes revealed no differences, subject groups were com-
dependent enhancement of CSF cortisol level. Sub-
bined for further analysis. When groups were combined,
jects with the APOE-⑀2 allele, which decreases the
two-way ANOVA revealed a marked effect of APOE geno-
risk for AD,15 had the lowest CSF cortisol concentra-
type on CSF cortisol such that APOE-⑀4/⑀4 ⬎ ⑀3/⑀4 ⬎ ⑀3/⑀3
tions. These findings demonstrate effects of APOE
⬎ ⑀2/⑀3 (F[3,93] ⫽ 7.8, p ⫽ 0.0001) (see figure 2). Post hoc
genotype on HPA axis activity that may have neuro-
pairwise comparisons revealed differences (all p ⬍ 0.05) in
CSF cortisol concentration among all APOE genotypes
biological implications for AD.
with the exception of APOE-⑀3/⑀3 versus APOE-⑀2/⑀3. ApoE is abundant in steroidogenic tissues, and in
There was no effect of gender on CSF cortisol and no inter- the human adrenal cortex, apoE is synthesized at a
action of gender and APOE genotype. relative rate equal to or greater than that observed
CSF and plasma cortisol relationships. Plasma corti- in the liver.26 ApoE in the adrenal cortex is thought
sol determinations were available for 26 of the 34 control to play a role in lipid redistribution among cells and
subjects and 44 of the 64 AD subjects. Plasma and CSF regulation of the utilization of cholesterol for steroid
cortisol levels were positively correlated in all subjects (r ⫽ production.27,28 Human APOE gene expression in cul-
0.39, p ⫽ 0.001). Plasma cortisol concentrations and rela- tured Y1 adrenocortical cells results in a marked
tionship between CSF and plasma cortisol did not differ decrease in both basal and adrenocorticotrophic
between AD and control subject groups or by APOE hormone-induced steroidogenesis29,30 and alterations
genotype. in cholesterol metabolism favoring storage over utili-
CSF cortisol and cognitive function. There was no cor- zation.31 Characterization by high-resolution two-
relation between MMSE scores and CSF cortisol level dimensional gel analysis has indicated that isoforms
within the subjects with AD (r ⫽ 0.172, p ⫽ 0.19). There of human adrenocortical apoE correspond exactly to
1096 NEUROLOGY 56 April (2 of 2) 2001
the specific isoforms of plasma apoE.26 These find- allele appears to accelerate the pathobiological pro-
ings suggest that the association of the APOE allele cess that culminates in AD25 and is associated with
with CSF cortisol concentration that we have found increased cognitive decline37 and hippocampal vol-
may be the result of differing efficacies of the apoE- ume loss,39 these effects of the APOE-⑀4 allele are
⑀2, ⑀3, and ⑀4 isoforms in inhibiting adrenal steroido- not observed once AD becomes apparent. It has been
genesis. Direct investigation of the isoform-specific repeatedly reported in most40-44 but not all45 longitu-
effects of apoE on adrenal steroidogenesis is neces- dinal studies of AD progression and APOE genotype
sary to confirm this hypothesis. that there is no effect of the APOE-⑀4 allele on the
Increased HPA axis activity in AD, manifested by rate of AD progression. The lack of effect of the ⑀4
increased cortisol concentrations in plasma and allele on the rate of progression in AD remains an
urine1-8 and resistance to suppression of plasma cor- unexplained paradox regardless of the mechanisms
tisol by the synthetic glucocorticoid dexamethasone,32,33 responsible for the effect of the ⑀4 allele to increase
is perhaps the most consistently demonstrated physio- the risk of AD. If high CSF cortisol concentration
logic dysregulation in this disorder.34 That elevated were involved in the mechanisms by which a nonde-
glucocorticoid concentrations induced by stress pro- mented person “converts” to AD, one would expect
duce hippocampal neurodegenerative changes in the that high CSF cortisol level in a nondemented person
rat and tree shrew9-11 and that aging-associated hip- destined to develop AD would persist after AD be-
pocampal neurodegeneration can be prevented by ad- comes clinically evident. This issue can be resolved
renalectomy in the rat35 provide rationale for the only by prospective longitudinal studies.
hypothesis that excess cortisol in human aginglowers Several mechanisms have been hypothesized to
the threshold for the expression of neurodegenera- contribute to the role of APOE genotype in the
tion in AD. Because APOE genotype was not re- pathobiology of AD.46 For example, apoE 1) acts as a
ported in earlier studies demonstrating increased chaperone mediating ␤-amyloid protein aggregation,
HPA activity in AD,1-8 it is unknown if increased 2) binds to ␤-amyloid protein and mediates clearance
HPA axis activity in those AD samples studied was a via the apoE receptor, 3) is an injury response pro-
function of increased APOE-⑀4 frequency. tein, and 4) modulates neurite extension. The cur-
These results confirm and extend to living pa- rent results together with those from animal and
tients the observation in AD of increased cortisol other human studies raise the possibility that APOE
concentrations in CSF obtained post mortem.16 The genotype effects on the HPA axis may be involved in
concentration of cortisol in CSF provides a better the pathobiology of AD. The APOE-⑀4 allele may pro-
estimate of CNS exposure to cortisol than does the duce increases in cortisol similar to the aging-
concentration in blood as CSF cortisol is in direct dependent increases in corticosterone observed in
equilibrium with brain extracellular fluid. Further- APOE knockout mice. These APOE knockout mice
more, only ⬇5% of plasma cortisol is the free, biolog- also manifest CNS neurodegenerative changes.47,48 A
ically active form, unbound to corticosteroid-binding recent longitudinal study in older nondemented hu-
globulin or albumin;17 total plasma cortisol levels mans demonstrated a relationship between elevated
therefore do not necessarily accurately reflect free plasma cortisol concentrations, reduced hippocampal
cortisol concentration. CSF corticosteroid-binding volume, and cognitive impairment.39 Taken together,
globulin concentrations are ⬇0.3% of those in blood, these results provide rationale for longitudinal stud-
and very little CSF cortisol is bound to proteins.17,18 ies of nondemented older persons with the ⑀3/⑀4 ge-
Also, rapid penetration of free cortisol from blood notype. Such studies could determine if
into CSF, but slower clearance of cortisol from CSF nondemented ⑀3/⑀4 persons with high CSF cortisol
than from blood, results in higher and more pro- concentration are at greater risk for AD than ⑀3/⑀4
longed cortisol elevations in CSF than in serum after persons with low CSF cortisol concentration. If so,
episodic increases in HPA axis activity.19 such a result would support involvement of APOE
The lack of a relationship between cognitive func- genotype effects on CSF cortisol concentrations in
tion and CSF cortisol level in the subjects with AD the pathobiological processes associated with AD.
makes it unlikely that higher CSF cortisol level re-
flects disease severity; rather, it is more consistent Acknowledgment
with the increased frequency of the APOE-⑀4 allele The authors acknowledge the excellent technical assistance of
and decreased frequency of the APOE-⑀2 allele Molly Wamble, Rebekah Rein, Robert Beckham III, and Elizabeth
Colasurdo.
within the AD group. A recent study reported a sim-
ilar lack of correlation between plasma cortisol and
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