Cerebrospinal Fluid Tau and Amyloid: How Well Do These Biomarkers Reflect Autopsy-Confirmed Dementia Diagnoses?

Abstract

Tau and beta-amyloid (Abeta) are proposed diagnostic biomarkers for Alzheimer disease (AD). Previous studies report their relationship to clinical diagnoses of AD and other dementias. To understand their value as predictors of disease-specific pathology, levels determined during life must be correlated with definitive diagnoses in mixed dementia groups and cognitively normal subjects.
To correlate antemortem cerebrospinal fluid (CSF) tau and Abeta levels with definitive dementia diagnosis in a diverse group of patients; to calculate statistics for CSF tau and Abeta.
Prospective study.
Ten clinics experienced in the diagnosis of neurodegenerative dementias. Patients One hundred six patients with dementia and 4 cognitively normal subjects with a definitive diagnosis, and 69 clinically diagnosed cognitively normal subjects.
Correlation of CSF tau and Abeta with final diagnosis.
Mean tau level was 612 pg/mL for the 74 patients with AD, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for 3 patients with dementia with Lewy bodies, and 140 pg/mL for 73 cognitively normal control subjects. Tau was less than 334 pg/mL for 20 patients with AD. Abeta42 was reduced in patients with AD (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with dementia with Lewy bodies (14 fmol/mL) or prion disease (60 fmol/mL).
Elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. However, some patients with AD have a level less than the mean +/- 2 SDs of the cognitively normal cohort.

Full text

Cerebrospinal Fluid Tau and ␤-Amyloid
How Well Do These Biomarkers Reflect Autopsy-Confirmed Dementia Diagnoses?
Christopher M. Clark, MD; Sharon Xie, PhD; Jesse Chittams, MS; Douglas Ewbank, PhD; Elaine Peskind, MD;
Douglas Galasko, MD; John C. Morris, MD; Daniel W. McKeel, Jr, MD; Martin Farlow, MD; Sharon L. Weitlauf, RN;
Joseph Quinn, MD; Jeffrey Kaye, MD; David Knopman, MD; Hiroyuki Arai, MD, PhD; Rachelle S. Doody, MD, PhD;
Charles DeCarli, MD; Susan Leight, BS; Virginia M.-Y. Lee, PhD; John Q. Trojanowski, MD, PhD
Background: Tau and ␤-amyloid (A␤) are proposed di-
agnostic biomarkers for Alzheimer disease (AD). Previ-
ous studies report their relationship to clinical diag-
noses of AD and other dementias. To understand their
value as predictors of disease-specific patholody, levels
determined during life must be correlated with defini-
tive diagnoses in mixed dementia groups and cogni-
tively normal subjects.
Objectives: To correlate antemortem cerebrospinal fluid
(CSF) tau and A␤levels with definitive dementia diag-
nosis in a diverse group of patients; to calculate statis-
tics for CSF tau and A␤.
Design: Prospective study.
Setting: Ten clinics experienced in the diagnosis of neu-
rodegenerative dementias.
Patients: One hundred six patients with dementia and
4 cognitively normal subjects with a definitive diagnosis,
and 69 clinically diagnosed cognitively normal subjects.
Main Outcome Measures: Correlation of CSF tau and
A␤with final diagnosis.
Results: Mean tau level was 612 pg/mL for the 74 pa-
tients with AD, 272 pg/mL for 10 patients with frontal
dementia, 282 pg/mL for 3 patients with dementia with
Lewy bodies, and 140 pg/mL for 73 cognitively normal
control subjects. Tau was less than 334 pg/mL for 20 pa-
tients with AD. A␤42 was reduced in patients with AD (61
fmol/mL) compared with patients with frontal demen-
tia (133 fmol/mL) and control subjects (109 fmol/mL),
but not compared with patients with dementia with Lewy
bodies (14 fmol/mL) or prion disease (60 fmol/mL).
Conclusions: Elevated CSF tau levels are associated with
AD pathology and can help discriminate AD from other
dementing disorders. However, some patients with AD
have a level less than the mean±2 SDs of the cognitively
normal cohort.
Arch Neurol. 2003;60:1696-1702
ALZHEIMER DISEASE (AD) is
a neurodegenerative dis-
order that produces pro-
gressive impairments in
memory, language, judg-
ment, insight, behavior, and personality.
Pathological features include neurofibril-
lary tangles composed of hyperphosphory-
lated tau, neuritic plaques composed of
␤-amyloid (A␤) fibrils, and neuronal death
with associated cerebral atrophy and glio-
sis. These pathological changes are most
prominent in the hippocampus, entorhi-
nal cortex, and association areas of the neo-
cortex and are believed to be responsible
for the clinical features.1
The clinical diagnosis of probable AD
requires the presence of dementia symp-
toms characterized by a history of pro-
gressive memory loss and decline in one
or more other areas of cognition that is suf-
ficient to interfere with everyday func-
tioning, documentation of the cognitive
impairment with psychometric testing, and
the exclusion of alternative explanations
for the dementia syndrome.2On the ba-
sis of prospective longitudinal clinical-
pathological studies performed primarily
in academic centers specializing in memory
disorders, the clinical diagnosis of AD has
a positive predictive value of 84%, a nega-
tive predictive value of 66%, a sensitivity
of 90%, a specificity of 56%, and a posi-
tive likelihood ratio of 2.9.3Data from com-
munity-based studies often report a lower
sensitivity and specificity.4,5 This is be-
cause clinical diagnostic accuracy often is
confounded when the core symptoms of
AD are shared by other pathologically dis-
tinct neurodegenerative dementias. In ad-
dition, cognitive impairment may be dif-
ficult to assess reliably in individuals with
low education and in those who cannot be
tested in their preferred language. Fi-
ORIGINAL CONTRIBUTION
Author affiliations are given at
the end of the article.
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nally, because most dementing illnesses impair insight,
clinicians usually must obtain additional information from
someone who knows the individual well. The combina-
tion of these factors may delay a patient’s evaluation and
present difficulties establishing a correct diagnosis dur-
ing the earliest symptomatic stage of the illness. The de-
velopment of new therapies for AD, particularly those that
target the core pathologic features, increases the need to
improve diagnostic accuracy and efficiency, particu-
larly during the earliest phase when attempts to halt or
slow the progression are most appropriate.6-10
Tau and A␤are components of the core neuropatho-
logical changes of AD that can be measured in the cere-
brospinal fluid (CSF) and have been the most fre-
quently studied of the candidate diagnostic biomarkers.11,12
They have been measured in patients with a variety of
clinically diagnosed conditions,13,14 yet there is limited
information relating premortem levels to a pathologi-
cally established diagnosis.
The purpose of this study was to determine the CSF
levels of tau and A␤in individuals undergoing an evalu-
ation for dementia in university specialty clinics and to
compare these levels with their confirmed diagnosis based
on the presence of a disease-causing mutation, a protein
marker (eg, 14-3-3) in a typical clinical presentation, or
the neuropathological findings at autopsy. In addition,
CSF tau and A␤from a group of cognitively normal el-
derly subjects observed longitudinally who have not come
to autopsy provided a second reference cohort.
METHODS
Clinicians experienced in the diagnosis of neurodegenerative
dementias participated in this study. Eight of the 10 clinics were
Clinical Cores of Alzheimer’s Disease Centers funded by the
National Institute on Aging of the National Institutes of Health,
Bethesda, Md. The subjects included 107 patients undergoing
a clinical evaluation for dementia, 4 pathologically confirmed
normal elderly control subjects, and 69 cognitively normal el-
derly subjects with 2 to 8 years of longitudinal follow-up since
their lumbar puncture (LP).
Appropriate consent was obtained from all subjects or their
caregivers in accordance with protocols approved by the insti-
tutional review board at each participating site.
CLINICAL EVALUATION
All participants received a standard neurologic evaluation, in-
cluding cognitive testing. Additional clinical and laboratory tests
were done at the discretion of the evaluating physician. Con-
trols were comprehensively assessed to ensure the absence of
dementia. Although specific methods varied among the sites,
all controls were assessed using clinical and cognitive mea-
sures that are standard in the field (eg, Mini-Mental State Ex-
amination [MMSE]; psychometric batteries and functional as-
sessments) at entry and follow-up examinations.
Cerebrospinal fluid was obtained by standard clinical pro-
cedures. All samples were free of blood contamination. For some
subjects, the LP was done as part of a separate research study.
For others, CSF was obtained as part of their routine clinical evalu-
ation. Residual CSF aliquots were stored in polypropylene tubes
at −80°C at the participating site and then transferred on dry ice
to the Center for Neurodegenerative Disease Research at the Uni-
versity of Pennsylvania, Philadelphia, where they were main-
tained at −80°C until assayed for tau and A␤peptides.
ASSIGNMENT OF THE DEFINITIVE DIAGNOSIS
The definitive diagnosis was based on the findings at autopsy
or the identification in a symptomatic patient of a genetic mu-
tation known to cause AD, Gerstmann-Straussler-Scheinker syn-
drome, or Huntington disease. All 5 patients with a diagnosis
of Creutzfeldt-Jakob disease had a typical clinical picture and
either a positive CSF 14-3-3 marker15 (2 patients) or neuro-
pathological findings of Creutzfeldt-Jakob disease at autopsy
(3 patients). The final diagnosis for the 104 subjects who came
to autopsy was assigned by the study neuropathologist (J.Q.T.)
after a review of the pathological findings and without knowl-
edge of the CSF results.
GENETIC MUTATIONS
Participating sites used established methods to identify disease-
causing mutations in the amyloid precursor protein, preseni-
lin 2, prion, or Huntington genes (for a review, see Rosenberg
et al16).
CSF TAU ANALYSIS
Cerebrospinal fluid tau levels were determined by a sandwich
enzyme-linked immunosorbent assay (Innotest hTAU-Ag; In-
nogenetics Nv, Ghent, Belgium) that uses the phosphorylation-
independent anti-tau capture antibody AT120 and phosphory-
lation-independent monoclonal antibodies HT7 and BT2 as
reporting antibodies.17 The assay was done as described pre-
viously18 and without knowledge of the clinical or pathologi-
cal diagnosis.
CSF A␤ANALYSIS
Cerebrospinal fluid A␤levels were determined by the sand-
wich enzyme-linked immunosorbent assay developed by Su-
zuki et al19 as described previously.18 This assay provides a sepa-
rate quantitative measure for all A␤peptides ending at amino
acid residue 40 (A␤40) and those ending at amino acid 42 (eg,
1-42 and 17-42). Briefly, a monoclonal antibody raised to A␤1-16
(BAN50) served as the capture antibody, and monoclonal an-
tibodies raised to A␤40 (BA27) or to A␤35-43 (BC05) as the re-
porting antibodies to detect A␤40 and A␤42, respectively. The
assay for CSF A␤40 and A␤42 levels was done without knowl-
edge of the subject’s diagnosis.
STATISTICAL ANALYSIS
Differences between mean tau and A␤levels across groups were
evaluated with the 2-sample ttest. Associations between pa-
tient characteristics and tau or A␤levels within the whole AD
group were examined by multiple linear regressions. A step-
wise model selection procedure was used to select the final mod-
els. The covariates of interest included sex, age at symptom on-
set, age at LP, duration of symptoms at the time of LP, MMSE
score when the CSF was obtained, and apolipoprotein E geno-
type. The effect of clinical center was also considered. The as-
sumptions of ttest and multiple linear regressions were checked.
Because the distribution of tau values was skewed, a logarith-
mic transformation was applied when 2-sample ttest and re-
gression analyses were performed so that the normality as-
sumption of these analyses could be met.
The reliability of the CSF tau and A␤data was estimated
by repeating the analysis of selected samples and comparing
the means and the correlation between the 2 assays. Standard
decision statistics such as specificity, sensitivity, and positive
predictive value were generated by means of a logistic regres-
sion model.20 We used CSF tau as a predictor in the logistic
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regression model when generating decision statistics for tau.
We used A␤as a predictor in the logistic regression model when
generating decision statistics for A␤. When comparing the 2
areas under the receiver operating characteristic (ROC) curve,
we used the algorithm suggested by DeLong et al.21
All statistical analyses were performed with the SAS22 and
STATA23 software systems. Unless otherwise stated, all statis-
tical tests are 2-sided and have a .05 significance level.
RESULTS
STUDY COHORT
Demographic and clinical information is presented in
Table 1 and Table 2. The cohort had a mean of 14 years
of education (range, 6-20 years) and was primarily white
(95%). The diagnostic categories, average age at symp-
tom onset, duration of dementia symptoms at the time
of LP, and duration of symptoms before death are pre-
sented in Table 1.
The AD group included 10 patients with Lewy body
variant of AD (LBVAD), 3 patients with an amyloid pre-
cursor protein mutation, and 1 with a presenilin 2 mu-
tation. Five of the 8 patients with prion disease had
Creutzfeldt-Jakob disease and 3 had Gerstmann-
Straussler-Scheinker syndrome. All 11 patients in the
“Other” category had clinical signs and symptoms of de-
mentia. They included 3 with progressive supranuclear
palsy and 1 each with Huntington disease (verified by
an expanded CAG repeat in the Huntington gene), mo-
tor neuron disease, bipolar depression, nondominant an-
terior temporal lobe ganglioglioma, ischemic vascular de-
mentia, multiple sclerosis, progressive multifocal
leukoencephalopathy, and Parkinson disease.
CSF TAU VALUES
Since we performed 5 mean comparisons for CSF tau level,
we adjusted the significance level from .05 to .01 by means
of Bonferroni correction.
The mean (±SD) CSF tau level for the 60 patients
with pathologically proven nongenetic AD without Lewy
bodies was 627±446 pg/mL. While this level was above
the mean level of 449±258 pg/mL for the 10 patients with
LBVAD, there was no statistically significant difference
at the .01 level between the 2 values (P=.30).
With the use of a cutoff value of 234 pg/mL, CSF
tau had a sensitivity of 85%, specificity of 84%, positive
predictive value of 87%, and positive likelihood ratio of
5.3 to correctly distinguish patients with AD from cog-
nitively normal control subjects (Figure 1).
Compared with values in the cognitively normal co-
hort, the mean CSF tau level was slightly elevated in 2
diagnostic groups that can be difficult to separate from
AD on clinical grounds: frontal dementia (FD) (272±120
Table 1. Cohort Demographics
Diagnostic
Category
No. of
Subjects
Age at Dementia Onset,
Mean (SD), y
Age at LP,
Mean (Range), y
Years of Symptoms
at Time of LP,
Mean (SD)
Duration of Symptoms
Before Death,
Mean (SD), y
AD 74 63 (11.2) 69 (37-90) 5.9 (4.9) 10 (5.4)
Control subjects*73 NA 71 (52-87) NA NA
DLB 3 71 (8.5) 74 (70-79) 2.9 (3.8) 9 (2.0)
FD 10 61.2 (11.6) 66 (44-81) 5.4 (3.6) 8 (5.4)
Prion disease† 8 60 (7.1) 63 (56-73) 3.2 (4.0) 5 (5.2)
Other 11 63.6 (9.2) 67 (44-82) 3.9 (3.4) 6 (5.0)
Abbreviations: AD, Alzheimer disease; DLB, dementia with Lewy bodies; FD, frontal dementia; LP, lumbar puncture; NA, not applicable.
*Includes 4 subjects with autopsy confirmation.
†Includes Creutzfeldt-Jakob disease (n = 5) and Gerstmann-Staussler-Scheinker syndrome (n = 3).
Table 2. Tau Values by Diagnostic Category
Diagnosis No. of Subjects
Tau, pg/mL
Log Tau, Mean (SD)Mean (SD) Range
AD 60 627 (446) 89-2206 6.21 (0.70)
LBVAD 10 449 (258) 108-1006 5.97 (0.55)
Genetic AD*4 784 (487) 361-1422 6.52 (0.63)
AD all† 74 612 (430) 89-2206 6.20 (0.68)
Controls‡ 73 140 (97) 59-500 4.73 (0.64)
DLB 3 282 (22) 257-300 5.64 (0.08)
FD 10 272 (120) 93-427 5.50 (0.51)
Prion§ 8 2302 (2300) 118-6908 7.06 (1.47)
Other 11 403 (372) 119-1239 5.71 (0.74)
Abbreviations: AD, Alzheimer disease; DLB, dementia with Lewy bodies; FD, frontal dementia; LBVAD, Lewy body variant of Alzheimer disease.
*Amyloid precursor protein mutations (n = 3) and presenilin 2 mutation (n = 1).
†Includes LBVAD and genetic AD.
‡Includes 4 subjects with autopsy confirmation.
§Includes Creutzfeldt-Jakob disease (n = 5) and Gerstmann-Straussler-Scheinker syndrome (n = 3).
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pg/mL) and dementia with Lewy bodies (DLB) (282±22
pg/mL). For each of these 2 groups, the mean tau value
was significantly different at .01 level from the mean value
for the AD group as a whole (FD vs AD [all], P=.002;
DLB vs AD [all], P⬍.001), but not significantly differ-
ent at .01 level for the cohort with LBVAD (FD vs LBVAD,
P=.06; DLB vs LBVAD, P=.10) (Table 2). With the use
of a more diagnostically challenging mixture of patients
with AD, FD, and DLB, a cutoff value for CSF tau of 361
pg/mL had a sensitivity of 72%, specificity of 69%, posi-
tive predictive value of 80%, and positive likelihood ra-
tio of 3.1 to correctly distinguish those with AD from the
patients with FD and DLB (Figure 2).
Three of the 7 patients with cognitive impairment
and elevated tau levels in the “Other” pathological cat-
egory had neurologic diseases that are readily distin-
guished from AD by standard clinical criteria. These in-
cluded 1 patient each with motor neuron disease (1116
pg/mL), temporal lobe ganglioglioma (1239 pg/mL), and
progressive multifocal leukoencephalopathy (381 pg/mL).
The individual values for each patient in the “Other” neu-
rologic disease category are presented in Table 3.
Within the AD cohort, there was no relationship be-
tween the patient’s CSF tau level, apolipoprotein E geno-
type, degree of cognitive impairment as indicated by their
MMSE score, or the proportion of the patient’s total du-
ration of illness at the time of LP (onset to LP/onset to
death) that had passed by the time the CSF was ob-
tained (linear regression analyses, data not reported). In
the entire AD cohort (n=74), there was an inverse cor-
relation between the duration of dementia symptoms at
the time of LP and the level of tau in the CSF (P⬍.03).
On average, there was a 4% decline in tau level for each
additional year of symptoms.
Despite the difference in the average CSF tau val-
ues between the AD group and the other pathologically
defined diagnostic groups, there was considerable over-
lap with respect to individual subject values. Twelve (16%)
of the 74 patients with a confirmed diagnosis of AD had
CSF tau values of 234 pg/mL or less, including 3 of the
10 patients with LBVAD.
CSF A␤VALUES
The ␤-amyloid values are presented in Table 4. While
we found the expected reduced A␤42 in the AD cohort
compared with cognitively normal subjects, the addi-
tion of this information did not add to the diagnostic value
of tau level when compared by a nonparametric ap-
proach.21 Specifically, there was no meaningful increase
in the area under the curve when the ROC curve for the
combination of tau and ␤-amyloid levels was compared
with the ROC curve for tau level alone. For patients with
AD vs cognitively normal controls, the AUC was 0.937
for tau level alone and 0.942 for tau plus ␤-amyloid lev-
els (P=.71). For patients with AD vs the combined FD
and DLB cohort, the AUC was 0.798 for tau level alone
and 0.809 for tau plus ␤-amyloid levels (P=.60). Simi-
lar results were seen regardless of whether the absolute
A␤42 or percentage A␤42 values were used. Likewise, re-
stricting the AD cohort to patients whose tau values were
below 470 pg/mL (the median cohort value) or below the
1.0
0.8
0.6
0.4
0.2
0.0
0.0 0.2 0.6
0.4 0.8 1.0
1
–
Specificity
Sensitivity
Statistics Associated With Tau
=
361 pg/mL
Sensitivity
=
72%
Specificity
=
69%
Area Under the Curve
=
0.798
Tau
=
361 pg/mL
Figure 2. Receiver operating characteristic curve: sensitivity and specificity
of cerebrospinal fluid tau to correctly categorize patients with Alzheimer
disease (n= 74) and those with frontal dementia or Lewy body dementia
(n= 13).
Table 3. Individual Values for Subjects
With Miscellaneous Neurologic Conditions
Diagnosis Tau, pg/mL A␤42,%*A␤42, fmol/mL
ALS dementia 1116 5.3 68
Depression 372 6.0 60
Ganglioglioma 1239 2.7 7
HD 259 10.1 225
IVD 296 6.2 164
MS 232 4.2 78
PML 381 6.2 63
PD 119 16.8 44
PSP 160 21.7 59
PSP 122 14.8 30
PSP 313 NA NA
Abbreviations: A␤42,␤-amyloid 42–amino acid peptide; ALS, amyotrophic
lateral sclerosis; HD, Huntington disease; IVD, ischemic vascular dementia;
MS, multiple sclerosis; NA, not available; PML, progressive multifocal
leukoencephalopathy; PD, Parkinson disease; PSP, progressive supranuclear
palsy.
*A␤42/(A␤42 +A␤40) expressed as a percentage.
1.0
0.8
0.6
0.4
0.2
0.0
0.0 0.2 0.6
0.4 0.8 1.0
1
–
Specificity
Sensitivity
Statistics Associated With Tau
=
234 pg/mL
Sensitivity
=
85%
Specificity
=
84%
Area Under the Curve
=
0.937
Tau
=
234 pg/mL
Figure 1. Receiver operating characteristic curve: sensitivity and specificity
of cerebrospinal fluid tau to correctly categorize patients with Alzheimer
disease (n= 73) and cognitively normal subjects (n= 74).
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ROC cutoff value failed to demonstrate added value for
the A␤42 measurement (data not shown).
Within the AD cohort, there was no relationship be-
tween the absolute A␤42 level or percentage A␤42 and the
patient’s sex, age at symptom onset, age at LP, duration
of symptoms at the time of LP, MMSE score at the time
of LP, or apolipoprotein E genotype. However, there was
a weak association (borderline significant) between the
percentage A␤42 and the degree of cognitive impairment
as judged by their MMSE score (P=.04). A 1-point in-
crease in MMSE was associated with 0.14% decrease in
percentage A␤42.
To evaluate the effect of storage time on A␤levels,
we examined 33 stored samples obtained over a 3-year
period from a separate cohort of patients with a variety
of dementing conditions. The initial values of the samples
spanned the range of percentage A␤levels (mean, 4.6%;
range, 2.1%-12.4%) found for most of the subjects in the
autopsy cohort and had an average storage time since first
assayed of 326 days (range, 50-832 days). The mean per-
centage A␤42 did not change significantly (from 4.77%
to 5.03%; range of changes, 0.1%-3.0%), indicating that
the value was not significantly affected by storage at −80°C.
The correlation between the values for the first and sec-
ond assay was 0.88.
COMMENT
Our study addressed the relevance of CSF tau and A␤
levels in the differential diagnosis of AD by comparing
premortem CSF values with the definitive diagnosis in a
well-characterized and diverse group of patients with de-
mentia. We confirmed an association between elevated
CSF tau levels premortem and the pathological hall-
marks of AD, indicating that high CSF tau levels, in the
appropriate clinical setting, strongly supports a diagno-
sis of AD. Nevertheless, some patients who meet clini-
cal and pathological criteria for AD had CSF tau levels
below the balanced sensitivity-specificity ROC cutoff value
of 234 pg/mL. Determining the A␤level by means of the
Suzuki et al enzyme-linked immunosorbent assay did not
improve the diagnostic accuracy. Therefore, CSF tau and
A␤values cannot be used to exclude a diagnosis of AD
in a patient who meets consensus criteria of the Na-
tional Institute of Neurological and Communicative Dis-
orders and Stroke–Alzheimer’s Disease and Related Dis-
orders Association for that diagnosis.
We used an assay that recognized total levels of CSF
tau. It remains to be seen whether assays using an anti-
body targeting a phosphorylated tau epitope24-28 will im-
prove the specificity of CSF tau for a definitive diagno-
sis of AD.
The source of CSF tau remains unclear but most
likely is related to the degeneration of neurofibrillary
tangle–laden neurons. The protein has not been well char-
acterized in the CSF and may exist in fragmented forms.29
There is no information on the steady-state kinetics of
CSF tau in normal individuals. Although a recent report
indicates that it may require 3 to 5 months for elevated
CSF tau levels to return to normal after an acute stroke,30
the clearance rate of tau from the CSF in patients with
neurodegenerative dementia remains unknown.
The average tau value for the group with LBVAD in
our study was lower than the value for patients with AD
free of Lewy body pathological findings. Although the
reason for this has yet to be established, the finding is
consistent with reports that these patients have fewer neu-
rofibrillary tangles and more amyloid plaques than pa-
tients with AD without LB pathological findings.
Several conditions that are clinically distinct from
AD are associated with marked elevations in CSF tau level,
including acute stroke,30-32 multiple sclerosis,33 AIDS de-
mentia,34 and head trauma.35 In addition, in our study,
patients with amyotrophic lateral sclerosis and ganglio-
glioma had elevated values.
Elevated CSF tau levels have also been reported in
patients with clinical diagnoses of corticobasal degen-
eration36 and one,37 but not all, studies of FD.38,39 These
2 neuropathologically distinct dementias can be diffi-
cult to distinguish from AD on clinical criteria alone. In
addition, several of our patients with prion diseases had
high CSF tau and low A␤42 values that overlapped with
Table 4. A␤42 Values by Diagnostic Category
Diagnosis No. of Subjects
A␤42,%*A␤42, fmol/mL
Mean (SD) Range Mean (SD) Range
AD sporadic 60 7.1 (4.3) 0.2-22.0 67.0 (127.8) 0-872
LBVAD 10 8.2 (3.7) 0.9-12.6 20.2 (11.7) 3-43
Genetic AD† 4 5.2 (3.5) 1.8-9.8 77.8 (60.0) 27-152
AD (all)‡ 74 7.1 (4.1) 0.2-22.0 61.3 (116.8) 0-872
Controls§ 73 6.0 (2.9) 1.4-16.6 109.4 (61.2) 28-379
DLB 3 8.0 (2.4) 6.1-10.7 13.7 (6.4) 9-21
FD 10 7.5 (3.4) 2.1-13.4 132.6 (117.6) 5-414
Prion㛳8 8.5 (3.7) 4.0-16.3 59.6 (40.8) 2-131
Other 11 9.5 (6.0) 2.7-21.7 84.7 (64.0) 7-225
Abbreviations: A␤42,␤-amyloid 42–amino acid peptide; AD, Alzheimer disease; DLB, dementia with Lewy bodies; FD, frontal dementia; LBVAD, Lewy body
variant of Alzheimer disease.
*A␤42/(A␤42 +A␤40) expressed as a percentage.
†Includes mutations on amyloid precursor protein (n = 3) and presenilin 2 (n = 1).
‡Includes sporadic, genetic, and LBVAD.
§Includes 4 subjects with autopsy confirmation.
㛳Includes Creutzfeldt-Jakob disease (n = 5) and Gerstmann-Straussler-Scheinker syndrome (n = 3).
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those found for patients with AD. The CSF tau level is
known to be elevated in many, but not all, patients with
Creutzfeldt-Jakob disease.40
The CSF A␤42 levels were less informative than CSF
tau levels in this study cohort. Our finding of a reduced
ratio of A␤42 to total A␤in the CSF of patients with AD
is consistent with previous reports in clinically diag-
nosed cohorts.14,41-45 However, because of the broad range
of values found in this study, neither the absolute level
of A␤42 nor the percentage A␤42 in CSF provided mean-
ingful additional diagnostic information when the tau level
was elevated.
An important limitation of our study is the use of
patients undergoing an evaluation in a specialty referral
clinic. Nevertheless, the descriptive characteristics of our
subjects are similar to those reported in other clinical-
pathological studies of patients with dementia in di-
verse settings. The inclusion of 3 patients with AD with
an amyloid precursor protein mutation and 1 with a pre-
senilin 2 mutation made the average age at onset for the
members of our AD group lower than typically re-
ported, but it broadened the populations in which these
CSF data have been gathered.
The emergence of disease-specific therapy and the
prospect of treatment to stabilize and perhaps reverse the
neuropathological changes associated with AD46,47 lend
urgency to the effort to identify and characterize patho-
logically specific biomarkers. In general, an expert clini-
cal diagnosis of probable AD is pathologically verified in
85% to 90% of patients who come to autopsy. The abil-
ity of clinicians to reliably predict the absence of AD patho-
logical changes is not as good.3Our study suggests that
elevated CSF tau level may be helpful in distinguishing
AD from other forms of dementia, including neurode-
generative disorders such as FD and DLB. These studies
are less helpful in identifying patients with AD with con-
comitant Lewy bodies or in differentiating AD from prion
diseases.
Accepted for publication June 18, 2003.
From the Departments of Neurology (Dr Clark) and
Pathology and Laboratory Medicine (Drs Lee and Tro-
janowski and Ms Leight), Center for Neurodegenerative Dis-
ease Research (Drs Lee and Trojanowski and Ms Leight),
Alzheimer’s Disease Center (Drs Clark, Xie, Ewbank, and
Trojanowski), Institute on Aging (Drs Clark and Tro-
janowski), Center for Clinical Epidemiology and Biostatis-
tics (Dr Xie and Mr Chittams), and Population Studies Cen-
ter (Dr Ewbank), University of Pennsylvania, Philadelphia;
Department of Psychiatry and Behavioral Sciences and Alz-
heimer’s Disease Research Center, University of Washing-
ton, Seattle (Dr Peskind); Department of Neurology and Alz-
heimer’s Disease Research Center, University of California
at San Diego (Dr Galasko); Departments of Neurology (Dr
Morris) and Pathology (Drs Morris and McKeel) and Alz-
heimer’s Disease Research Center (Drs Morris and
McKeel), Washington University, St Louis, Mo; Depart-
ment of Neurology and Alzheimer’s Disease Center, Indi-
ana University, Indianapolis (Dr Farlow and Ms Weit-
lauf); Department of Neurology and Alzheimer’s Disease
Research Center, Oregon Health Sciences University, Port-
land (Drs Quinn and Kaye); Department of Neurology, Mayo
Clinic, Rochester, Minn (Dr Knopman); Department of Geri-
atric Medicine, Tohoku University, Sendai, Japan (Dr Arai);
Department of Neurology and Alzheimer’s Disease Re-
search Center, Baylor College of Medicine, Houston, Tex (Dr
Doody); and Department of Neurology, Kansas Univer-
sity, Kansas City (Dr DeCarli).
Author contributions: Study concept and design (Drs
Clark, Galasko, Morris, and Farlow); acquisition of data
(Drs Peskind, Galasko, Morris, McKeel, Farlow, Quinn,
Kaye, Knopman, Arai, Doody, and DeCarli and Mss Weit-
lauf and Leight); analysis and interpretation of data (Drs
Xie, Ewbanks, Galasko, Doody, DeCarli, Lee, and Tro-
janowski and Mr Chittams); drafting of the manuscript (Drs
Clark, Xie, Galasko, Farlow, Arai, and DeCarli); critical
revision of the manuscript for important intellectual con-
tent (Drs Xie, Ewbanks, Peskind, Galasko, Morris,
McKeel, Farlow, Quinn, Kaye, Knopman, Doody, Lee,
and Trojanowski, Mr Chittams, and Mss Weitlauf and
Leight); statistical expertise (Dr Xie and Ewbanks and Mr
Chittams); obtained funding (Drs Morris and Knop-
man); administrative, technical, and material support (Drs
Peskind, McKeel, Arai, DeCarli and Mss Weitlauf and
Leight); study supervision (Drs Clark, Farlow, Quinn, Lee,
and Trojanowski).
This study was funded in part by grants AG10124 (Uni-
versity of Pennsylvania, Philadelphia); AG05136, AG08419,
and the Department of Veterans Affairs (University of Wash-
ington, Seattle); AG05131, AG05136, AG08419, and the De-
partment of Veterans Affairs (University of California, San
Diego); AG03991 and AG05681 (Washington University,
St Louis, Mo); AG08664 (Baylor College of Medicine, Hous-
ton, Tex); AG08017 (Oregon Health Sciences University,
Portland); and AG10133 (Indiana University, Indianapo-
lis) from the National Institutes of Health, Bethesda, Md.
We are grateful to the following pathologists for the
autopsy findings: James B. Leverenz, MD, and David No-
chlin, MD, University of Washington; Bernardino Ghetti,
MD, Indiana University; and H. Brent Clark, MD, PhD, Uni-
versity of Minnesota, Minneapolis; and to John Csernan-
sky, MD, Washington University, for providing CSF samples.
Corresponding author: Christopher M. Clark, MD,
University of Pennsylvania, Penn-Ralston Center,
3615 Chestnut St, Philadelphia, PA 19104 (e-mail:
clarkc@mail.med.upenn.edu).
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