Neurobiology of Aging 21 (2000) 735–740

www.elsevier.com/locate/neuaging

Relationship between apoE genotype and CSF ␤-amyloid (1– 42) and
tau in patients with probable and definite Alzheimer’s disease
Tero Tapiolaa, Tuula Pirttilaa, Pankaj D. Mehtab, Irina Alafuzoffa,c, Maarit Lehtovirtaa,
¨
Hilkka Soininena,*
a

Department of Neuroscience and Neurology, University Hospital and University of Kuopio, P.O.Box 1627, Fin-70211, Kuopio, Finland
b
Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
c
Department of Pathology, University Hospital and University of Kuopio, P.O.Box 1627, Fin-70211, Kuopio, Finland
Received 31 January 2000; received in revised form 11 April 2000; accepted 16 May 2000

Abstract
We investigated the usefulness of cerebrospinal fluid (CSF) ␤-amyloid42 (A␤42), ␤-amyloid40 (A␤40) and tau analyses in the diagnosis
of Alzheimer’s disease (AD). The study included 41 definite AD cases, 80 patients with probable AD, 27 with other dementias and 39
neurological controls. A␤42, A␤40 and tau protein concentrations in CSF were measured of using ELISA assays. A␤42 levels were
decreased and tau increased in AD. Combination of A␤42 and tau resulted a sensitivity of 50.4% for AD and specificities of 94.8% for
controls and 85.2% for other dementias. Ninety-one percent of the patients with A␤42 below the cutoff value (340 pg/ml) and tau above
the cutoff value (380 pg/ml) had AD. AD patients carrying apoE ⑀4 allele had lower A␤42 (P Ͻ 0.005) and higher tau (P Ͻ 0.05) levels
than those without an ⑀4 allele, and 18 (81.8%) of the 22 AD patients who had normal A␤42 and tau levels were apoE ⑀4 allele non-carriers.
Low A␤42 and high tau concentration in CSF strongly support the diagnosis of AD. Measurement of A␤42 may help the early diagnosis
of cases at risk for AD such as apoE ⑀4 allele carriers. © 2000 Elsevier Science Inc. All rights reserved.
Keywords: Alzheimer’s disease; Dementia; Cerebrospinal fluid; CSF; Tau; ␤-amyloid; Apolipoprotein E

1. Introduction
Alzheimer’s disease (AD) is the most common form of
dementia in elderly people. Currently, the definite diagnosis
of the disease is based on neuropathological examination of
the brain. The clinical diagnosis of probable AD requires
extensive clinical neurologic examination, neuropsychological testing, a panel of laboratory tests, and computed tomography or magnetic resonance imaging of brain. Clearly,
a biomarker for AD would be valuable in confirming the
diagnosis, in monitoring the progression of the disease and
in evaluating the efficacy of therapy. Recently, a consensus
report on molecular and biochemical markers of AD suggested that a clinically useful biomarker should detect early
cases and distinguish other dementias from AD with a
sensitivity and specificity Ͼ80% [28]. An ideal biomarker

* Corresponding author. Tel.: ϩ358-17-173-012; fax: ϩ358-17-173019.
E-mail address: Hilkka.Soininen@uku.fi (H. Soininen).

should also find presymptomatic AD cases, reflect the neuropathology, and thus the progression of the disease.
Neuropathological changes in AD include amyloid
plaques, consisting mainly of ␤-amyloid peptides, and neurofibrillary tangles composed of intracellular paired helical
filaments, whose main component is abnormally phosphorylated tau protein [12]. Soluble ␤-amyloid peptides ending
at carboxy-terminal residues 40 (A␤40) or 42 (A␤42), and
tau protein can be detected in cerebrospinal fluid (CSF).
Previous studies reported elevated concentrations of tau
protein [29,30] and decreased levels of A␤42 [5,10,18,22,
25] in CSF of AD patients. However, the clinical use of
these markers in the diagnosis of AD is not established, and
no studies based on neuropathologically confirmed AD
cases or other dementia cases are available.
The presence of apolipoprotein E (apoE) ⑀4 allele is a
well-documented risk factor for AD [24], and the presence
of ⑀4 allele increases the confidence of the clinical diagnosis
of AD [13]. However, apoE genotyping in AD is not recommended, because it cannot establish a diagnosis [14].
Interestingly, some earlier studies have shown an effect of

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T. Tapiola et al. / Neurobiology of Aging 21 (2000) 735–740

Table 1
Patient demographics
N
Alzheimer’s disease
Probable
Definite
Other dementias
Neurological controls

Female/Male

Age

Age of onset

Duration
(years)

MMSE

121
80
41
27
39

84/37
46/34
38/3
14/13
19/20

75 Ϯ 10
71 Ϯ 8
84 Ϯ 9
73 Ϯ 9
61 Ϯ 10

71 Ϯ 10
68 Ϯ 9
76 Ϯ 9
71 Ϯ 10
—

5.1 Ϯ 4.4
2.6 Ϯ 1.9
9.7 Ϯ 4.2
1.9 Ϯ 1.4
—

14 Ϯ 10
20 Ϯ 5
1.7 Ϯ 3.3
20 Ϯ 6
—

Abbreviations used: N, number of cases; MMSE, Mini-Mental Status examination score. Results are mean values Ϯ SD.

apoE genotype on CSF ␤-amyloid [5] and tau [3,7,26],
whereas others have not found any relationship [2,11,18,
19].
Here, we analyzed levels of tau, A␤42, and A␤40 in CSF
from neuropathologically confirmed and probable AD patients, from patients with other dementias, and from neurological controls. We also examined the relationship of these
markers to apoE genotype and cognitive status.

2. Subjects and methods
2.1. Patients with dementia and neurological controls
The study included two groups of dementia patients
(patients with AD and other dementias, such as vascular
dementia (N ϭ 8), frontotemporal dementia (N ϭ 4), Lewy
body dementia (N ϭ 5), Parkinson’s disease with dementia
(N ϭ 3), and unclassified dementia (N ϭ 7)) and a control
group (patients with other neurological diseases or psychosomatic disorders). The patient demographics are shown in
Table 1. The diagnosis of AD was made according to the
criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and
Related Disorders Association (NINCDS-ADRDA) [15].
The AD group included 80 patients with probable AD and
41 patients with definite AD in whom the extent of histological Alzheimer’s degenerative changes was graded according to the criteria of the Consortium to Establish a
Registry for Alzheimer’s Disease (CERAD) [17]. The diagnoses of other dementias were based on the guidelines of
Diagnostic and Statistical Manual of Mental Disorders,
fourth edition (DSM-IV) [1]. The definite AD group consisted of patients derived from a follow-up study of hospitalized patients in the geriatric department of Harjula hospital in Kuopio. In this group the mean interval between
lumbar puncture and autopsy was 18 (SD 14) months. The
probable AD patients, patients with other dementias and
neurological controls were recruited from diagnostic investigations in the Department of Neurology, Kuopio University hospital. Determination of the apoE genotype was performed as previously described [8]. The study was approved
by the local ethics committee of the University of Kuopio
and Kuopio University Hospital, and informed consent for

participation in the study was obtained from all subjects and
caregivers of demented patients.
2.2. CSF samples and quantification of ␤-amyloid and tau
Lumbar CSF samples were obtained using a standardized
protocol. The 1 ml aliquots were immediately frozen and
stored at Ϫ70°C until assay. The analyses were carried out
without any knowledge about the clinical data, in duplicate.
To quantify levels of tau in CSF, a sandwich enzyme linked
immunoassay (ELISA) using the Innotest hTAU-Antigen
kit (Innogenetics, Belgium) was performed according to the
manufacturer’s protocol. ␤-amyloid concentrations were
quantified using a monoclonal antibody 6E10 and polyclonal antibodies R162 for A␤40 and R164 for A␤42 in
sandwich ELISAs, as described previously [16]. The detection limit was 20 pg/ml for A␤40 and 39 pg/ml for A␤42.
2.3. Statistical analysis
The data were analyzed by using SPSS for Windows
V.8.0.1 software. The one-way ANOVA with Bonferroni
post hoc analysis was used to compare differences in means
between the diagnostic groups. The Student’s t-test for
independent samples or Mann–Whitney test, when assumptions were not met, were used to compare differences in
means between two patient groups. Correlations were calculated using a two-tailed Pearson’s correlation test. The
statistical significance was set at P Ͻ 0.05. The relationship
between sensitivity and specificity was determined using
Receiver Operating Characteristics (ROC) curve (Fig. 1).

3. Results
The diagnostic groups differed in age (F(2,184) ϭ 30.2,
P Ͻ 0.001), patients with AD or other dementia being older
than neurological controls (Table 1). The Mini-Mental Status Examination (MMSE) scores or age of onset did not
differ significantly between probable AD and other dementia groups. Definite AD patients had lower MMSE scores
than probable AD patients (P Ͻ 0.001) or other dementia
patients (P Ͻ 0.001) and higher age of onset compared to
probable AD patients (P Ͻ 0.001).

T. Tapiola et al. / Neurobiology of Aging 21 (2000) 735–740

Fig. 1. Receiver operating characteristics at different cut off points of CSF
A␤42 and tau concentrations. The best results for sensitivity and specificity
were obtained using the cutoff points 340 pg/ml for A␤42 and 380 pg/ml
for tau (arrowheads).

Patients with definite AD had lower CSF A␤40 levels
(mean Ϯ SD: 2.0 Ϯ 0.7 ng/ml) compared to subjects in the
other groups (F(3,180) ϭ 16.5, P Ͻ 0.001). There were no
differences in A␤40 concentrations between the other
groups (mean Ϯ SD, Probable AD: 3.4 Ϯ 1.4 ng/ml, Other
dementias: 3.2 Ϯ 1.0 ng/ml, Controls: 3.1 Ϯ 0.7 ng/ml).
The CSF A␤42 concentration differed in the study
groups (F(3,183) ϭ 22.1, P Ͻ 0.001). The levels of A␤42
were decreased in definite (P Ͻ 0.001) and probable (P Ͻ
0.001) AD patients and in patients with other dementias
(P Ͻ 0.001) compared to those of non-demented controls

737

(Table 2). Although levels of A␤42 were lower in definite
and probable AD patients compared to patients with other
dementias, only the difference between definite AD and
other dementias achieved statistical significance (P Ͻ 0.05).
The cutoff value of 340 pg/ml (Fig. 1) for A␤42 distinguished probable AD patients with a sensitivity of 68.8%
(55/80) and definite AD with a sensitivity of 78.0% (32/41).
The specificities were 84.6% (33/39) for controls and 59.3%
(16/27) for other dementias (Fig. 2).
CSF tau concentrations were significantly increased in
patients with probable and definite AD compared to those of
neurological controls (F(3,183) ϭ 10.6, P Ͻ 0.001) (Table
2). However, there were no significant differences between
AD patients and patients with other dementias or between
other dementias and neurological controls. The cutoff point
of 380 pg/ml (Fig. 1) resulted in sensitivity of 62.5% (50/
80) for probable AD and 56.1% (23/41) for definite AD.
The specificities with this cutoff were 92.3% (36/39) for
controls and 66.7% (18/27) for other dementias.
Combination of CSF A␤42 and tau using the best cutoff
values (340 pg/ml for A␤42 and 380 pg/ml for tau) resulted
in sensitivities of 52.5% (42/80) for probable AD and 46.3%
(19/41) for definite AD. The specificities were 94.9% (37/
39) for controls and 85.2% (23/27) for other dementias (Fig.
2). Ninety-one percent (61/67) of patients with CSF A␤42
levels under 340 pg/ml and tau concentrations higher than
380 pg/ml had AD. The combination of CSF A␤42 and tau
levels resulted better specificity for diagnosis of AD than
the presence of an apoE ⑀4 allele [65.7% for controls (25/
38) and 59.3% for other dementias (16/27)].
Because CSF levels of A␤42 and tau were significantly
related to apoE genotype, these measurements yielded low
sensitivity for AD. AD patients with at least one apoE ⑀4
allele had significantly lower CSF A␤42 levels than those
without ⑀4 allele (P Ͻ 0.005) (Table 2). The lowest values

Table 2
CSF A␤42 and tau values of patients

␤-amyloid 1-42

Tau

All cases
Neurological controls
Alzheimer’s disease
Probable
Definite
Other dementias

␧4Ϫ

␧4ϩ

All cases

␧4Ϫ

␧4ϩ

516 Ϯ 162
(N ϭ 39)
280 Ϯ 168*
(N ϭ 121)
303 Ϯ 171*
(N ϭ 80)
234 Ϯ 153*
(N ϭ 41)
353 Ϯ 163*
(N ϭ 27)

522 Ϯ 136
(N ϭ 25)
349 Ϯ 191
(N ϭ 48)
397 Ϯ 202
(N ϭ 28)
280 Ϯ 154
(N ϭ 20)
384 Ϯ 153
(N ϭ 16)

500 Ϯ 211
(N ϭ 13)
235 Ϯ 135#
(N ϭ 73)
253 Ϯ 128#
(N ϭ 52)
189 Ϯ 142
(N ϭ 21)
307 Ϯ 173
(N ϭ 11)

256 Ϯ 110
(N ϭ 39)
516 Ϯ 332†
(N ϭ 121)
527 Ϯ 353†
(N ϭ 80)
494 Ϯ 290†
(N ϭ 41)
393 Ϯ 276
(N ϭ 27)

246 Ϯ 91
(N ϭ 25)
416 Ϯ 296
(N ϭ 48)
412 Ϯ 339
(N ϭ 28)
421 Ϯ 233
(N ϭ 20)
422 Ϯ 337
(N ϭ 16)

272 Ϯ 144
(N ϭ 13)
581 Ϯ 340‡
(N ϭ 73)
588 Ϯ 348‡
(N ϭ 52)
563 Ϯ 327
(N ϭ 21)
349 Ϯ 155
(N ϭ 11)

Abbreviations used: N, number of cases; ␧4Ϫ, patients without apolipoprotein E ␧4 allele; ␧4ϩ, patients carrying at least one apolipoprotein E ␧4 allele.
Results are mean values Ϯ SD.
* A␤42: C versus AD P Ͻ 0.001; C versus OD P Ͻ 0.001; def AD versus OD P Ͻ 0.05.
†
tau: AD versus C P Ͻ 0.001.
#
A␤42 ␧4Ϫ versus ␧4ϩ: all AD cases P Ͻ 0.005; prob. AD P Ͻ 0.005; def. AD P ϭ 0.057.
‡
tau ␧4Ϫ versus ␧4ϩ: all AD cases P Ͻ 0.05; prob. AD P Ͻ 0.05; def. AD P ϭ 0.118.

738

T. Tapiola et al. / Neurobiology of Aging 21 (2000) 735–740

were observed in AD patients with two ⑀4 alleles (mean Ϯ
SD, probable AD: 225 Ϯ 118 pg/ml, N ϭ 18; definite AD:
157 Ϯ 149 pg/ml, N ϭ 5). A similar trend was found also
in patients with other dementias, but differences between
apoE ⑀4 allele carriers and non-carriers did not, however,
reach statistical significance. Also, CSF tau levels were
higher in AD patients with at least one apoE ⑀4 allele
compared to those without an ⑀4 allele (P Ͻ 0.05). The
highest concentrations were detected in patients with two ⑀4
alleles (mean Ϯ SD, probable AD: 672 Ϯ 349 pg/ml, N ϭ
18; definite AD: 607 Ϯ 251 pg/ml, N ϭ 5).
Altogether eighteen of twenty-two AD patients who had
normal levels of A␤42 and tau were the apoE ⑀4 allele
non-carriers. We then calculated sensitivities and specificities separately for ⑀4 allele carriers and non-carriers. Among
⑀4 allele carriers, A␤42 analysis resulted in sensitivity of
80.7% (42/52) for probable AD and 90.5% (19/21) for
definite AD whereas sensitivities for ⑀4 allele non-carriers
were 46.4% (13/28) and 65% (13/20), respectively. The
corresponding values for tau were 75.0% (39/52; probable
AD) and 61.9% (13/21; definite AD) for ⑀4 allele carriers
and 39.3% (11/28) and 50.0% (10/20)for ⑀4 allele noncarriers, respectively.
A␤42 levels were decreased and tau levels elevated already in AD patients with mild dementia, MMSE scores Ն
24 (N ϭ 21, mean Ϯ SD A␤42: 366 Ϯ 182 pg/ml, P Ͻ
0.005, tau: 522 Ϯ 432 pg/ml, P Ͻ 0.05) compared to those
of control patients (Fig. 3). There was a positive correlation
of A␤42 and A␤40, but not tau levels, with MMSE scores
(1– 42: r ϭ 0.25, P Ͻ 0.01; 1– 40: r ϭ 0.50, P Ͻ 0.001) in
patients with AD.

4. Discussion

Fig. 2. Combination of CSF A␤42 and tau measurements in the diagnosis
of AD. Lines indicate the cut off points of 340 pg/ml for A␤42 and 380
pg/ml for tau. The high tau/low A␤42 quadrant resulted a sensitivity of
50.4% for AD (A). Twenty-two AD patients had similar A␤42 and tau
levels to controls (A), and 18 (81.8%) of them did not carry the apoE ⑀4
allele. Thirty-two of 39 neurological controls and 11 of 27 patients with
other dementias had high A␤42 and low tau concentration. The specificities
of the test were 94.8% for controls (A) and 85.2% for other dementias (B).
Two neurological control patients and four patients with other dementias
had similar A␤42 and tau levels as observed in AD (C).

The present study is the first one confirming a decrease in
CSF A␤42 concentrations and an increase in CSF tau protein concentrations in a large number of AD patients including 41 definite AD cases. Our data are consistent with
previous reports that have indicated that combination of
these biomarkers might be useful in supporting the diagnosis of AD, particularly in patients carrying genetic risk
factors for AD [5,10,18,29]. The relatively high specificity
of these analyses makes A␤42 and tau analysis a promising
laboratory test for the confirmation of the diagnosis of AD.
The combination of A␤42 and tau resulted in better specificity (90.9%) than apoE genotyping (63.1%) in the discrimination of AD patients from all other patients. Moreover,
our data suggest that CSF A␤42 levels reflect the progression of the disease.
Currently there are six studies, including the present one,
which have reported the combination of CSF A␤42 and tau
levels in AD [5,9,10,18,23] (Table 3). Sensitivities have
varied from 50% (our study) to 85% [9]. The reasons for the
discrepancies may be due to differences in the patient populations, particularly in the number of apoE ⑀4 allele carri-

T. Tapiola et al. / Neurobiology of Aging 21 (2000) 735–740

739

Table 3
Sensitivities and specificities of studies reporting combined CSF A␤42
and tau measurements in the diagnosis of Alzheimer’s disease
Sensitivity (%)

Specificity (%)

Motter et al. [18]
Kanai et al. [10]
Galasko et al. [5]

59%
71%
77%

Shoji et al. [23]
Hulstaert et al. [9]

69%
85%

Current study

50%

96%
83%
93%
65%
88%
86%
58%
95%
85%

(AD
(AD
(AD
(AD
(AD
(AD
(AD
(AD
(AD

versus
versus
versus
versus
versus
versus
versus
versus
versus

C ϩ OD)
C ϩ OD)
C)
OD)
C ϩ OD)
C)
OD)
C)
OD)

Abbreviations used: C, control group; OD, patients with other dementias.

Fig. 3. CSF A␤42 and tau concentrations in controls and in patients with
AD classified into three groups according their Mini-Mental Status examination (MMSE) scores. A␤42 (F(3,154) ϭ 25.1, P Ͻ 0.001) and tau
(F(3,154) ϭ 7.55, P Ͻ 0.001) levels differed in the groups. AD groups,
including patients with mild forms of the disease (MMSE Ն 24), had lower
A␤42 and higher tau levels compared to those of control patients. Patients
with severe AD (MMSE Յ 10) had the lowest A␤42 concentrations.

ers, and in the methodology used in the analyses. In our
study AD patients without the apoE ⑀4 allele had higher
CSF A␤42 and lower tau values than AD patients with an ⑀4
allele resulting in a significant overlap between the values in
AD patients without an ⑀4 allele and controls. The sensitivity of A␤42 measurement was 83.6% for AD patients
carrying an ⑀4 allele, whereas in AD patients without an ⑀4
allele it was only 54.2%. Many studies have shown that the
frequency of apoE ⑀4 allele is increased in familial and
sporadic AD, and it is well established that carriers of ⑀4
allele have an increased risk of developing AD [24]. Our
results suggest that the A␤42 might be useful for detection
of AD cases among those individuals carrying genetic risk
factors such as the apoE ⑀4 allele.
Specificity of the test was good because most patients
(91%) with low A␤42 and high tau levels in CSF had AD,
and only four of the 27 patients with other dementias had

the analogous CSF profile. The results suggest that the
combination of these biomarkers may be helpful for the
discrimination between AD and other dementias. There was
no consistent pattern of CSF profile in any other dementias
than AD. However, the number of patients with other dementias was low, and more extensive studies with neuropathologically confirmed cases are needed.
An ideal biomarker should reflect the pathogenic processes that contribute to the progression of the disease and
the neuropathological changes occurring in the brain tissue.
There are currently efficacious symptomatic therapies available for patients with mild or moderate AD [4,21]. Therefore, it is essential to detect AD as early as possible. Our
data are consistent with previous studies that have shown an
increase of tau [6,20,26] and a decrease of A␤42 [5,10]
levels in CSF from patients with mild AD. Moreover, CSF
A␤42 and A␤40 levels were the lowest in patients with
definite AD who had severe dementia and the longest duration of the disease. The results suggest that CSF ␤-amyloid levels may be associated with the progression of the
disease. We have also recently shown that CSF A␤42 and
A␤40 levels decreased in patients with probable AD after a
3-year follow-up period [27]. However, the relation between these biomarkers and neuropathological changes in
brain tissue is not well-understood, and the time of appearance of the first changes in CSF is not known.
In conclusion, many studies using a combination of CSF
A␤42 and tau have shown that these markers can differentiate AD patients from controls with a specificity ranging
from 86% to 96% (Table 3). Low levels of A␤42 and high
levels of tau in CSF strongly support the diagnosis of AD.
CSF A␤42 analysis may help to detect early cases of AD
particularly in individuals at risk for the disease such as
those patients with mild cognitive impairment and who
carry the apoE ⑀4 allele.
Acknowledgments
The study was supported by a grant from the Medical
Research Council of the Academy of Finland. We thank
Seija Hynynen for her skillful technical assistance.

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T. Tapiola et al. / Neurobiology of Aging 21 (2000) 735–740

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