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From: TSS (216-119-144-35.ipset24.wt.net)
Subject: Prion protein codon 129 polymorphism and risk of Alzheimer disease [FULL TEXT]
Date: July 29, 2004 at 9:26 am PST
-------- Original Message --------
Subject: Prion protein codon 129 polymorphism and risk of Alzheimer disease [FULL TEXT]
Date: Thu, 29 Jul 2004 11:01:31 -0500
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
######## Bovine Spongiform Encephalopathy #########
Prion protein codon 129 polymorphism
and risk of Alzheimer disease M. Riemenschneider, MD; N. Klopp, PhD; W. Xiang, PhD; S. Wagenpfeil,
PhD; C. Vollmert, PhD;
U. Müller, MD; H. Förstl, MD; T. Illig, PhD; H. Kretzschmar, MD; and A.
Kurz, MD
AbstractThe authors investigated the PRNP Met129Val polymorphism in
1,393 subjects including 482 patients with
Alzheimer disease (AD) and two independent control groups. In patients,
PRNP Met homozygosity conferred increasing risk
with decreasing age at onset (onset: 61 to 70 years, n 151, p 0.02,
odds ratio [OR] 1.72, 95% CI 1.2 to 2.53; onset: 60
years, n 138, p 0.013, OR 1.92, 95% CI 1.31 to 2.87), whereas no
association was obtained in patients with onset at
older than 70 years. The results suggest involvement of the prion
protein in the pathogenesis of early-onset AD.
NEUROLOGY 2004;63:364366
Alzheimer disease (AD) and CreutzfeldtJakob disease
(CJD) are neurodegenerative disorders that are
associated with protein deposits due to the conversion
of a soluble normal protein into an insoluble, aggregated
form that is neurotoxic. In CJD, the cellular
prion protein (PrPC), a glycoprotein of unascertained
function, is converted to the disease-associated aggregated
form (PrPSc), which is thought to be infectious.
From its cellular localization at synaptic vesicles and
the presence of four copper-binding motifs, a potential
role of PrPs in synaptic and antioxidant function has
been suggested. Whereas several mutations within
PRNP cause rare familial forms of prion diseases, homozygosity
for methionine (Met) or valine (Val) at the
coding PRNP codon 129 polymorphism is associated
with an increased risk of developing sporadic and iatrogenic
CJD.1 In contrast, individuals heterozygous for
the PRNP Met129Val polymorphism appear to be protected
or have a longer incubation period.2 The presence
of two identical amino acids at the PRNP codon
129 polymorphism may facilitate the PrP conversion
into the disease-associated, aggregated form, whereas
two different amino acids may hinder aggregation.3
At first sight, AD and CJD represent completely
different disease entities, but there are several lines
of evidence indicating that PrP may also be involved
in AD, suggesting common pathogenetic mechanisms.
Epidemiologic studies indicate familial clustering
of sporadic CJD with other neurodegenerative
diseases4; neuropathologic studies showed increased
PrP immunoreactivity in AD5; an association between
Val homozygosity at the PRNP codon 129
polymorphism and cognitive impairment in the elderly
has been demonstrated6; and an association
between homozygosity at the PRNP codon 129 polymorphism
and patients with early-onset AD (EOAD)
was reported, which was stronger for Val homozygotes
than Met homozygotes.7
Because of its potential importance, we investigated
the PRNP codon 129 polymorphism in a large
cohort of German patients with AD and two independent
age-matched control groups: a cognitively
healthy and a large population-based control group.
Methods. The study refers to a total of 1,393 subjects, composed
of 482 individuals with a clinical diagnosis of probable AD,8 189
cognitively healthy control subjects (Control Group I), and 722
age-matched individuals derived from a larger population-based
sample (Control Group II) (table 1). From the 482 patients with
AD, 217 subjects had an early onset (65 years) of the disease. All
patients and members of Control Group I were recruited from a
university memory clinic. Both control groups were matched for
geographic localization and ethnicity. Control Group I consisted of
cognitively healthy subjects who were recruited among spouses
and caregivers from the memory clinic and community-based geriatric
health care units. Control Group II consisted of elderly subjects
derived from a large population-based study (KORA) from
Augsburg, which is close to Munich. The study protocol was approved
by the review board of the medical faculty of Technische
Universität München. Genotyping of the PRNP Met129Val polymorphism
was performed by matrix-assisted laser desorption
time-of-flightbased mass spectrometry of allele-specific primer
extension products (Sequenom, San Diego, CA). Differences in
genotype distributions between patients and control subjects were
analyzed by logistic regression analysis using age and sex as covariates.
The attributable risk was calculated using the logistic
odds ratio (OR) estimate. According to the PrP model, we also
From the Neurochemistry and Neurogenetics Laboratory (Dr.
Riemenschneider), Department of Psychiatry and Psychotherapy (Drs.
Förstl and Kurz), and
Department of Medical Statistics and Epidemiology (Dr. Wagenpfeil),
Technische Universität Munich, Institute of Epidemiology (Drs. Klopp,
Vollmert, and
Illig) and Genome Analysis Center (Drs. Klopp and Illig), GSF Research
Center for Environment and Health, MunichNeuherberg, Department of
Neuropathology (Drs. Xiang and Kretzschmar), Ludwig Maximilians
Universität München, and Institute of Human Genetics (Dr. Müller),
University of
Giessen, Germany.
Supported by the Bundesministerium für Bildung und Forschung of Germany
Functional Genome Network grants: 01GS0166 TP3B Functional Genomics of
Alzheimer Disease (M. Riemenschneider, A. Kurz, and U. Müller); 01GS0166
TP4 Prion Diseases (H. Kretzschmar and Otto Windl). Genotyping was
performed in the Genome Analysis Center of the GSF Research Center for
Environment and Health and was partially funded by the German National
Genome Research Net (NGFN) Platform 6. Phenotyping of the KORAS2000
cohort was supported by the KORA Study Group: A. Döring, T. Illig, H.
Löwel, C.
Meisinger, B. Thorand, H.E. Wichmann (GSF National Research Center for
Environment and Health, Institute of Epidemiology); R. Holle, J. John (GSF
National Research Center for Environment and Health, Institute of Health
Economics and Health Care Management).
Received November 14, 2003. Accepted in final form March 11, 2004.
Address correspondence and reprint requests to Dr. M. Riemenschneider,
Neurochemistry and Neurogenetics Laboratory, Department of Psychiatry and
Psychotherapy, Technische Universität München, Ismaningerstr. 22, 81675
Munich, Germany; e-mail: m.riemenschneider@lrz.tu-muenchen.de
364 Copyright © 2004 by AAN Enterprises, Inc.
analyzed statistical differences using the heterozygous Met/Val
genotype as reference.
Results. The genotype distributions of the patient and
both control groups, which met HardyWeinberg expectations,
are presented in table 2. Comparison of the PRNP
codon 129 genotype frequencies between patients with AD
and both control groups showed a weak overrepresentation
of Met/Met homozygotes in patients with AD compared
with Control Group II (p 0.038, OR 1.3, 95% CI 1.01
to 1.59). This effect appeared to be stronger in patients
without the APOE 4 allele and in patients with EOAD
irrespective of the APOE genotype (Control Group I: p
0.029, OR 1.59, 95% CI 1.07 to 2.36; Control Group II:
p 0.028, OR 1.43, 95% CI 1.03 to 1.93) (see table 2).
Subgroup analysis according to the age at onset (70, 61
to 70, 60 years) identified an increase of PRNP Met allele
frequency and the attributable risk conferred by the Met
genotype with decreasing age at onset (table 3). With use
of the heterozygote genotype as reference, patients with
EOAD homozygous for either Met or Val were at a higher
risk (OR 1.61, 95% CI 1.1 to 2.3), as were patients
homozygous for Met (OR 1.65, 95% CI 1.1 to 2.5) (see
table 2).
No significant differences for the Val/Val genotype between
all patients or EOAD patients with a family history
of dementia (47%; Val/Val frequency 13.8%) and the
control subjects were found. In addition, we did not observe
a significant effect of the PRNP genotypes on ages at
onset using the complete or any patient subsample.
Discussion. Previous reports concerning the
PRNP codon 129 polymorphism and AD, particularly
EOAD, prompted us to examine this polymorphism
in the German population.7 In this sample, we identified
the Met genotype to confer risk to patients
with EOAD, which increased with decreasing age at
onset independently of APOE genotype. We observed
no association in patients with late-onset AD. Stratification
of the complete patient sample and the lateonset
AD group according to the APOE genotype
revealed higher PRNP Met genotype frequencies in
patients lacking the APOE 4 allele. Although this
patient sample appears large enough to allow subgroup
analyses, data derived from stratification procedures
must be interpreted with caution and
therefore should not be overrated. However, our findings
suggest a stronger contribution of the PrP to the
pathogenesis of EOAD. No significant association
was obtained for the Val/Val genotype, although we
observed a slight increase in patients with a positive
family history. The fact that we could not identify
any effect of PRNP genotypes on ages at onset may
be most likely due to a lack of statistical power as we
Table 1 Description of the patient and control samples
Diagnosis n
Age, y;
mean SD
Onset, y;
mean SD Sex, M/F
Alzheimer disease 482 69.9 10.2 66.8 10.2 206/277
Early onset, 65 y 217 60.7 6.3 57.5 5.7 112/105
Late onset, 65 y 265 77.5 5.7 74.5 5.6 97/168
Control Group I 189 67.1 11.9 73/116
Control Group II 722 63.8 8.3 310/412
Table 2 PRNP Met129 Val genotype, allele frequencies, and combined
homozygous genotypes in patients and controls
Group n
Genotype
Allele
frequency Combined genotype
M/M % M/V % V/V % M V MM VV %
AD 482 230 47.7 198 41.1 54 11.2 0.68 0.32 284 58.9
APOE 4 249 126 50.6 94 37.8 29 11.6 0.69 0.31 155 62.2
APOE 4 233 104 44.6 104 44.6 25 10.7 0.67 0.33 129 55.4
EOAD 217 111 51.2 83 38.2 23 10.6 0.70 0.3 134 61.8
APOE 4 117 60 51.3 42 35.9 15 12.8 0.69 0.31 75 64.1
APOE 4 100 51 51.0 41 41.0 8 8.0 0.72 0.28 59 59
LOAD 265 118 44.5 116 43.8 31 11.7 0.66 0.34 149 56.2
APOE 4 132 66 50.0 52 39.4 14 10.6 0.70 0.30 80 60.6
APOE 4 133 53 39.8 63 47.4 17 12.8 0.64 0.36 70 52.6
Control I 189 75 39.7 89 47.1 25 13.2 0.63 0.37 100 52.9
Control II 722 299 41.4 324 44.9 99 13.7 0.64 0.36 398 55.1
AD Alzheimer disease; EOAD early-onset Alzheimer disease (onset 65
y); LOAD late-onset Alzheimer disease (onset 65 y);
M Met; V Val.
July (2 of 2) 2004 NEUROLOGY 63 365
had to analyze the complete patient sample to detect
an effect of the much stronger APOE 4 allele.
Our results correspond partially with a recent
study from the Netherlands where an association
between PRNP codon 129 homozygosity, particularly
for Val, and patients with EOAD was reported.7 Although
we analyzed much larger sample sizes, we
did not observe any significant difference for the Val
genotype even when focusing our analysis on patients
with a positive family history of AD. Possible
reasons for the discrepancies remain to be elucidated
but may include several factors such as different proportions
of familial cases, sample size effects, and, as
a minor point, population differences.
But the lack of association in patients with lateonset
AD is in agreement with a Spanish study that
also failed to find any association between the PRNP
codon 129 polymorphism and patients with mostly
late-onset AD.9
In combination with previous results,7 homozygosity
at the PRNP codon 129 polymorphism seems to
be a genetic risk factor for EOAD. However, the underlying
pathologic mechanism may be different
from the currently discussed PrP model, which
states that homozygosity facilitates the conversion
from the normal protein (PrPc) into the infectious
form (PrPSc).1 In human prion disease, Met homozygosity
is associated with a relatively late onset of
disease but is also associated with a very short
course of clinical disease once it has started.10 Thus,
homozygosity for methionine seems to confer some
accelerating effect on neurodegenerative diseases.
But in contrast to CJD, disturbances of other biologic
functions of the PrP, like alterations of normal synaptic
functioning and an impaired defense against
oxidative stress, may account for the association
with EOAD. References
1. Palmer M, Dryden A, Hughes J, Collinge J. Homozygous prion protein
genotype predisposes to sporadic CreutzfeldtJakob disease. Nature
1991;352:340342.
2. Mead S, Stumpf M, Whitfeld J, et al. Balancing selection at the prion
protein gene consistent with prehistoric Kurulike epidemics. Science
2003;300:640643.
3. Petchanikow C, Saborio G, Anderes L, Frossard M, Olmedo M, Soto C.
Biochemical and structural studies of the prion protein polymorphism.
FEBS Lett 2001;509:451456.
4. van Duijn C, Delasnerie-Laupretre N, Masullo C, et al. Case-control
study of risk factors of CreutzfeldtJakob disease in Europe during
199395. European Union (EU) Collaborative Study Group of
CreutzfeldtJakob disease (CJD). Lancet 1998;351:10811085.
5. Voigtländer T, Klöppel S, Birner P, et al. Marked increase of neuronal
prion protein immunoreactivity in Alzheimers disease and human
prion diseases. Acta Neuropathol 2001;101:417423.
6. Berr C, Richard F, Dufouil C, Amant C, Alperovitch A, Amouyel P.
Polymorphism of the prion protein is associated with cognitive impairment
in the elderly The EVA Study. Neurology 1998;51:734737.
7. Dermaut B, Croes E, Rademakers R, et al. PRNP Val129 homozygosity
increases risk for early onset Alzheimers disease. Ann Neurol 2003;53:
409412.
8. McKhann G, Folstein M, Katzman R, Price D, Stadlan EM. Clinical
diagnosis of Alzheimers disease: report of the NINCDS-ADRDA Work
Group under the auspices of Department of Health and Human Services
Task Force on Alzheimers Disease. Neurology 1984;34:939944.
9. Combarros O, Sánchez-Guerra M, Llorca J, et al. Polymorphism at
codon 129 of the prion protein gene is not associated with sporadic AD.
Neurology 2000;55:593595.
10. Parchi P, Giese A, Capellari S, et al. Classification of sporadic
CreutzfeldtJakob disease based on molecular and phenotypic analysis
of 300 subjects. Ann Neurol 1999;46:224233.
Table 3 Risk conferred by Met/Met genotype according to age at onset
AD onset, y n
Allele frequencies Reference: Control Group I Reference: Control Group II
PRNP Met APOE 4 p OR (95% CI) AR, % p OR (95% CI) AR, %
70 192 0.64 0.27 0.82 1.06 (0.691.62) 5.7 0.8 1.11 (0.831.48) 9.9
6170 151 0.70 0.34 0.02 1.72 (1.22.53) 42 0.05 1.43 (1.012.01) 30
60 138 0.71 0.26 0.013 1.92 (1.312.87) 48 0.008 1.68 (1.192.39) 41
The p values (uncorrected), odds ratio (OR), and attributable risk (AR)
were calculated by logistic regression analysis with age and sex
as covariates using Control Groups I and II as reference.
AD Alzheimer disease.
366 NEUROLOGY 63 July (2 of 2) 2004 ######### http://mailhost-alt.rz.uni-karlsruhe.de/warc/bse-l.html ##########
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