Traumatic Brain Injury As A Risk Factor for Alzheimer Disease : Comparison of Two Retrospective Autopsy Cohorts with Evaluation of ApoE Genotype

BMC Neurology (2001) 1:3
http://www.biomedcentral.com/1471-2377/1/3
BMC Neurology (2001) 1:3
Research article
Traumatic brain injury as a risk factor for Alzheimer disease.
Comparison of two retrospective autopsy cohorts with evaluation
of ApoE genotype
Kurt A Jellinger*1, Werner Paulus2, Christian Wrocklage2 and Irene Litvan3
Address: 1L.Boltzmann Institute of Clinical Neurobiology, Baumgartner Hoehe 1, B-Bldg., A-1140 Vienna, Austria, 2Department of
Neuropathology, University of Munster School of Medicine, Munster, Germany and 3Cognitive Neuropharmacology Unit, H.M. Jackson
Foundation, Bethesda, Md, USA
E-mail: Kurt A Jellinger* - kurt.jellinger@univie.ac.at; Werner Paulus - werner.paulus@uni-muenster.de;
Christian Wrocklage - christian.wrocklage@uni-muenster.de; Irene Litvan - ilitvan@dvhip.org
*Corresponding author
Published: 30 July 2001
Received: 29 June 2001
Accepted: 30 July 2001
BMC Neurology 2001, 1:3
This article is available from: http://www.biomedcentral.com/1471-2377/1/3
© 2001 Jellinger et al; licensee BioMed Central Ltd. Verbatim copying and redistribution of this article are permitted in any medium for any non-com-
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Abstract
Background and Purpose: The impact of traumatic brain injury (TBI) on the pathogenesis of
Alzheimer disease (AD) is still controversial. The aim of our retrospective autopsy study was to
assess the impact of TBE and ApoE allele frequency on the development of AD.
Material and Methods: We examined 1. the incidence of AD pathology (Braak stageing,
CERAD, NIA-Reagan Institute criteria) in 58 consecutive patients (mean age ± SD 77.0 ± 6.8 years)
with residual closed TBI lesions, and 2. the frequency of TBI residuals in 57 age-matched autopsy
proven AD cases. In both series, ApoE was evaluated from archival paraffin-embedded brain
material.
Results: 1. TBE series: 12.1 % showed definite and 10.3% probable AD (mean age 77.6 and 75.2
years), only 2/13 with ApoE?3/4. From 45 (77.6%) non-AD cases (mean age 78.2 years), 3 had
ApoE?3/4. The prevalence of 22.4% AD in this small autopsy cohort was significantly higher than
3.3% in a recent large clinical series and 14% in the general population over age 70. 2. In the AD
cohort with ApoE?4 allele frequency of 30% similar to other AD series, residuals of closed TBI
were seen in 4 brains (7%) (mean age ± SD 78.2 ± 6.4), all lacking the ApoE?4 allele. TBI incidence
was slightly lower than 8.5% in the clinical MIRAGE study.
Conclusions: The results of this first retrospective autopsy study of TBI, ApoE? allele frequency,
and AD confirm clinical studies suggesting severe TBI to be a risk factor for the development AD
higher in subjects lacking ApoE?4 alleles. Further studies in larger autopsy series are needed to
elucidate the relationship between TBI, genetic predisposition, and AD.
Introduction
the pathogenesis of AD is still controversial. Accumulat-
While some genetic risk factors, e.g. apolipoprotein
ing epidemiological evidence implicates TBI as a risk fac-
(ApoE)?4, predispose the elderly to develop Alzheimer
tor for the subsequent development of AD [for rev. see
disease (AD), the role of traumatic brain injury (TBI) in
[1,2], while others reported no such association [see

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[3,4]. In the MIRAGE study, head injury as a risk factor
ApoE alleles was performed in all cases of both cohorts
for AD appeared greater among subjects lacking ApoE?4
from archival paraffin-embedded brain material using a
[5]. Among longitudinal studies [6–9], two reported a
semi-nested PCR method [19]. Since ApoE genotyping
significantly increased riks of developing AD in subjects
was performed retrospectively in cohort 1, no controls
with previous history of TBI [8,9] A recent study of 1776
for older, non-TBI subjects were available. Statistical
US World War II navy veterans showed that moderate
evaluation was performed using Chi-square test and the
and severe TBI in early adulthood, rated by the duration
Mann-Whitney U-test.
of loss of consciousness or posttraumatic amnesia, was
associated with increased risk of AD and dementia in late
Results
life (assessed by clinical protocols). The risk increased
1. TBE series
with the severity of the TBI and showed a nonsignificant
Among the 58 autopsy cases over age 60 with residuals
trend towards a stronger association between AD and
of closed TBI of various degrees and distribution, 7
TBI in men with ApoE?4 alleles [9]. Although it is well
brains or 12.1% (4 males and 3 females aged 69 to 83,
established that deposition of amyloid ? peptide (A?)
mean ± SD 77.6 ± 6.4 years, revealed the pathological fea-
known to play an important role in the pathogenesis of
tures of definite AD, i.e. Khachaturian positive, CERAD
AD, in fatal TBI is associated with an ApoE?4 allele
B or C, Braak stages 5 or 6, with a great likelihood of AD
[10,11] and that TBI may induce tau pathology with the
as cause of dementia according to the NIA-Reagan crite-
formation of neurofibrillary tangles, another major his-
ria. Only one of them exhibited ApoE?4, all the others
tological marker of AD [12,13], the mechanisms by which
were ?3/3 and ?2/3 (3 each). All these brains, in addition
TBI may induce the formation of AD pathology are still
to severe neuritic AD pathology showed posttraumatic
unknown, and several interpretations have been pro-
lesions of limited extent and various distribution, mainly
posed [13,14]. Whereas previous case-control and longi-
old contusions in bilateral frontobasal areas (n = 1), fron-
tudinal epidemiological studies on the association
totemporal (n = 1), right frontobasal and temporal(n = 2)
between TBI and AD were exclusively based on clinical
with additional old cerebellar contusion (n = 2), and
protocols, we present here data of a retrospective autop-
right frontal pole (n = 1). TBI history dated back 10 to 30
sy study on the relations between TBI residual lesions,
years prior to the death, but was unknown in 2 of these
ApoE allele frequency, and AD pathology.
patients. The duration of AD ranged from 4 to 7 years.
Two additional AD cases – 2 males aged 69 and 82 years,
Material and Methods
respectively – were excluded since the TBI due to falls
We examined two autopsy series from the research files
had occurred 2 to 4 months prior to death after the devel-
of the Ludwig Boltzmann Institute of Clinical Neurobiol-
opment of severe dementia. Both brains showed definite
ogy brain bank, Vienna, Austria, between 1977 and 2000.
AD (CERAD C, Braak stage 5); both were ApoE ?2/3.
This material was mainly derived from a large teaching
Further 6 cases or 10.3% (3 men and women each, aged
hospital with associated chronic hospital (together
65-85, mean ± SD 75.2 ± 6.4 years) were pathologically
around 3000 beds) in Vienna, Austria. In this retrospec-
classified "probable" AD, meeting positive Khachaturian
tive study, exact informations about IQ, education, and
criteria, CERAD B, Braak 3 or 4; with intermediate like-
other major risk factors for AD were not available. 1. In a
lihood of AD as cause of dementia according to the NIA-
consecutive series of 58 patients over age 60 (mean ± SD
Reagan criteria; only one of them had ApoE?3/4 allele,
77.0 ± 6.8) years with residual closed TBI pathology we
the others ?3/3 or ?2/3. In these patients, closed TBI had
looked for the incidence of AD pathology. 2. In a consec-
occurred between 8 and 39 years prior to death and
utive series of 57 age-matched autopsy proven AD cases
many years before development of cognitive impair-
(mean ± SD age 77.6 ± 7.3 years) we looked for the pres-
ment, the duration of which ranged from 3 to 7 years.
ence of morphological TBI residuals. All patients were
Neuropathology, in addition to AD lesions, revealed bi-
Caucasians and immunocompetent. All brains were ex-
lateral old traumatic contusional deficits or scars in
amined histologically using routine stains including
frontobasal and temporopolar areas (n = 2), in the right
modified Bielschowsky silver stain and immunohisto-
frontopolar and temporal, and in the left frontobasal and
chemistry with a battery of antibodies against ABl-42,
temporal or in the left parietal region (2 cases each).
PHF tau (antibody AT-8), ubiquitin, and ?-synuclein for
None of these subjects had a history of chronic alcohol-
the demonstration of Lewy bodies. The classification of
ism, Korsakoff syndrome or any morphological signs of
AD was performed according to the Khachaturian crite-
Wernicke encephalopathy or essential concomitant cere-
ria [15], the Consortium to Establish a Registry for Alzhe-
brovascular lesions except for occasional mild lacunar
imer Disease (CERAD) criteria [16], the Braak stageing
state in the basal ganglia. None of them meet the mor-
of neuritic Alzheimer lesions [17], and the National Insti-
phological criteria for mixed type dementia (combina-
tute on Aging (NIA)-Reagan Institute classification for
tion of AD and vascular encephalopathy), of Parkinson
the postmortem diagnosis of AD [18]. Evaluation of
disease (PD) or of dementia with Lewy bodies (DLB) [20].

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In the remaining 45 non-AD cases (77.6%; 36 men and 9
those older than 70, and between 7 and 50% for subjects
women aged 61 to 85, mean ± SD 78.2 ± 7.8 years), the
older than 85 years [26–31]. In comparison to AD pa-
ApoE allele frequency was ?3/3 (n = 39), ?3/4 and ?2/3
tients showing an ApoE?4 prevalence of 24 to 38% [21–
(n = 3 each) comparable to that in the general aged pop-
25], it was only 15.4% in the present cohort of AD cases
ulation [21–23]. Old traumatic brain lesions in this co-
with residual TBI lesions. The extent and distribution did
hort were seen mainly in the frontobasal, frontopolar
not seem to influence later developrent of AD. Since in
and temporopolar areas, less frequently frontobasal and
the majority of the patients later developing AD, TBI his-
frontopolar or temporal/ temporopolar unilaterally or
tory 10 to 30 years prior to death and the mean age of
bilaterally. In two of these cases (aged 85 and 86 years),
these patients was comparable to the non-AD cases, one
neuropathology revealed additional PD of the Lewy body
might exclude the possibility that a greater injury may
type with no only very few cortical Lewy bodies, thus ex-
have a bigger effect on AD development, especially when
cluding DLB [20].
interacting with older age which is the most significant
factor in AD [see [1]]. Since in this retrospective study no
2. AD cohort
exact information on pre-morbid intellectual levels and
Among 57 consecutive autopsy cases of definite AD aged
education were available, no suggestions about brain re-
71 to 91 years with a mean ± SD of 77.6 ± 7.3 years the
serve capacity (BRC) as a potential moderating factor on
ApoeE?4 allele frequency was 30% (?4/4 n = 6; ?3/4 n =
risk variables related to AD expression can be made.
11) which was comparable to that in other AD series
ranging from 24 to 38% [21–25]; all the others were ?3/
The prevalence of residuals of previous closed TBI in 7%
3 or 2/3. Residuals of closed TBI were seen in 4 brains or
of a consecutive series of autopsy-proven AD aged 71 to
7.0 %, 2 men and women each aged 71-91 (mean ± SD
91 (mean 77.6 ± 7.3) years, all lacking an ApoE?4 allele,
78.2 ± 5.6) years, all lacking ApoeE?4 alleles. They had
was slightly lower than in the large clinical MIRAGE
suffered closed head injuries 7 to 54 years prior to death
study, where TBI with loss of consciousness in AD
and, like in cohort 1, many years before onset of cognitive
probands was reported in 8.5% [5]. This study like ours
deterioration. A male dying at age 71 years has suffered a
indicates that closed head injury is a higher risk factor for
blow to the right parietal region with several hours un-
the development of AD among subjects lacking ApoE?4
consciousness 54 years prior to death; two women aged
alleles compared to those having them. This is in accord-
76 and 91 years had suffered TBI with unknown duration
ance with recent experimental data showing that trans-
of unconsciousness in car accidents 7 and 30 years before
genic mice expressing human ApoE?4 are more
death, and a male aged 75 years had TBI with short un-
susceptible than those expressing ApoE?3 to closed head
consciousness due to a fall on the occiput 8 years prior to
injury, probably related to a protective effect of ApoE?3
death, and a duration of AD of about 2 years. None of
and an ApoE?4-related pathological function [32].
them had experienced repeated TBI as boxers or other
sportsmen. Neuropathology, in addition to definite AD
In conclusion, the results of this first retrospective study
changes (Khachaturian positive, CERAD stage B or C,
on the association of TBI and ApoE allele frequency on
Braak stages 4 or 5, i.e. intermediate or high likelihood of
the development of AD confirm clinical studies suggest-
AD as the cause of dementia according to the NIA-Rea-
ing some influence of severe TBI on the development of
gan criteria), revealed old contusional scars in the
AD, being a higher risk factor for AD among subjects
frontobasal and temporal areas (n = 3) and in the pari-
lacking ApoE?4 alleles compared to those having them.
etal region (n = 1).
However, further studies in larger autopsy series of TBI
and AD are needed to further elucidate the relationshipt
Discussion
between closed TBI, ApoE allele, and the development of
To the best of our knowledge, this is the first study to de-
AD.
tect AD pathology in a consecutive autopsy series of post-
traumatic brain lesions and to look for the presence of
Competing interests
residual brain lesions of closed TBI in a cohort of autopsy
None Declared
proven AD cases. The prevalence of 22.3% of probable
and definite AD in a rather small cohort of subjects with
Acknowledgements
a mean age of 75 to 77.6 years and residuals of closed TBI
The authors are grateful to Mrs V. Rappelsberger for skilled laboratory
is considerably higher (p < 0.001) than 3.3% in the re-
work and to Mr E. Mitter-Ferstl, PhD, for secretarial assistance. The study
was funded in part by the Austrian Federal Ministery of Education and Sci-
cent clinical US series of VA subjects who sustained mod-
ence and by the Austrian Parkinson Society.
erate to severe TBI during World War II [9]. It was also
higher than the prevalence of AD in the general Cauca-
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Document Outline

• Research article
• Traumatic brain injury as a risk factor for Alzheimer disease. Comparison of two retrospective au...
• Abstract
• Introduction
  • Introduction
  • Material and Methods
  • Results
  • Discussion
  • Competing interests
  • Acknowledgements
  • References
    • Pre-publication history

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