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Apolipoprotein E genotypes in Parkinson's disease with and without dementia.

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Apolipoprotein E Genotypes in Parhnson's
Disease with and without Dementia
William C. Koller, MD, PhD," Sander L. Glatt, MD," Jean P. Hubble, MD," Anthony Paolo, PhD,"
Alexander I. Troster, PhD," Michael S. Handler, MD,? Rebecca T. Horvat, PhD,t Coleman Martin, BS,t
Karen Schmidt, BS," Annette Karst, RN," Ellen M. Wijsman, PhD,$ Chang-En Yu, PhD,S:
and Gerard D. Schellenberg, PhD#
The apolipoprotein E gene (Apo E) type 4 allele is a genetic risk factor influencing the development and age of onset
of Alzheimer's disease. Because Parkinson's disease shares many characteristics of Alzheimer's disease, we studied the
frequencies of Apo E genotypes in a cohort of 52 Parkinson's disease patients with dementia and 61 patients without
dementia. Dementia was determined per National Institute of Neurological and Communicative Disorders and Stroke
criteria and Mattis Dementia Rating Scale (DRS) < 126. Normal cognition was defined as DRS > 132. Apo E genotype
and allele frequencies did not differ between demented and nondemented parkinsonian patients. Neither group's
genotype and allele frequencies differed from that of a nondemented population of 78 controls. We conclude that the
Apo E ~4allele influences neither the development of Parkinson's disease nor the dementia associated with Parkinson's
disease.
Koller WC, Glatt SL, Hubble JP, Paolo A, Troster AI, Handler MS, Horvat RT, Martin C, Schmidt K,
Karst A, Wijsman EM, Yu C-E, Schellenberg GD. Apolipoprotein E genotypes in Parkinson's
disease with and without dementia. Ann Neurol 1995;37:242-245
The ~4 allele of apolipoprotein E gene (Apo E) is associated with late-onset Alzheimer's disease (AD) [ 1-41.
Furthermore the ~4 dosage has been found to correlate
with both increased risk and earlier age of onset of A D
C4).Thus Apo E appears to be a susceptibility gene or
risk factor that affects the rate of disease expressivity
of late-onset familial and sporadic AD. Suggested
mechanisms underlying Apo E ~4 effects in A D include enhancement of amyloid deposition in plaques
[5, 6 } and increased neurofibrillary protein deposition
in neuronal tangles 171.
Parkinson's disease (PD), like AD, is a neurodegenerative process. The two diseases share many common
characteristics and may have common determinants
[S]. Both conditions are age related and have some
common risk factors [9, lo}. A higher frequency of
secondary cases of P D among first-degree relatives of
A D cases [ 111 and similarly of secondary cases of AD
among first-degree relatives of P D [12} has been reported. Dementia frequently occurs in P D [13, 141
and, conversely, A D patients can exhibit parkinsonian
features 15, 161. Neuropathological features of the
two diseases overlap [17, IS} and cholinergic and dopaminergic deficiencies occur in both conditions [ 19,
20).
We determined Apo E genotypes in P D patients
with and without dementia to assess the role of this
genetic risk factor in PD.
From the Departments of "Neurology and tPathology, University
of Kansas Medical Center, Kansas City, KS, and Departments of
$Medicine and Biostaristics and $Neurology. University of Washington, Seattle, WA.
Received Apr 28, 1904, and in revised form Jul 15. Accepted for
publication Aug 2 5 , 1994.
242
Methods
Subjects with PI) were recruited from the PD Center at the
University of Kansas Medical Center, either from a longitudinal research study (AD Center) or from the PD clinic. Only
whites were studied because of reports of racial differences
in allele frequencies [ 3 ] . PD was defined by the presence of
two of the three cardinal features including tremor, rigidity
and bradykinesia, and sustained responsiveness to levodopa
therapy. Patients who developed clinically obvious cognitive
deficits prior to the motor deficits of P D and patients with
clinical features of progressive supranuclear palsy, ShyDrager syndrome, or olivopontocerebellar degeneration
were excluded. Controls were volunteers participating in a
longitudinal study of aging ( A D Center).
Clinical evaluation included the Unified Parkinson's Disease Rating Scale (UPDRS) and neurological examination.
Functional disability was assessed by the Blessed Dementia
Rating [ 2 I]. Neuropsychological evaluation included the
Mattis Dementia Rating Scale (DRS). Subjects were considered demented per National Institute of Neurological and
Communicative Disorders and Stroke (NINCDS) criteria
with total DKS score below 126 and cognitively related func-
Department of Neurologs,
correspondence to Dr
University of Kanhas Medical Center. 390 I Rainbow Blvd, Kansas
City, KS 66100-73 Id.
Copyright 6 1995 by the American Neurological Association
Results
Fifty-two P D patients met the criteria for the diagnosis
of dementia while 61 were identified as cognitively
intact (Table 1). There were 78 nondemented controls.
The demented patients were significantly older, had a
higher frequency of males, and had more advanced
disease as indicated by higher Hoehn-Yahr and
UPDRS scores than nondemented P D patients. Disease duration did not differ between the two groups.
There was no statistical difference in the distribution
of Apo E genotypes between the P D patients with and
without dementia (Table 2 ) . The genotypes of both
groups also did not differ from that of the control
population (Table 2). Comparison of Apo E allele frequencies also showed no difference between PD
with dementia, P D without dementia, and the control
population (Table 3). The genotypes and allele frequencies in our control population were similar to that
reported for the general population [ 2 3 ] . The regression analysis of DRS on Apo E genotype, age, and sex
identified age and sex, but not Apo E genotype, as
significant predictors of DRS (Table 4). The results
obtained with Apo E genotype coded as presencelabsence of ~4 were virtually identifical to those obtained
with Apo E genotype coded as number of e4 alleles,
so only the former are presented.
tional disability. Subjects were considered to be cognitively
intact if their DRS score was above 132. Control subjects
were not included unless their DRS was above 132.
G-enotyping
Genomic D N A was prepared from white cell pellets and
extracted with phenol and chloroform. Apo E genotypes
were determined without knowledge of subject's clinical status using primers, polymerase chain reaction (PCR) conditions, and dot-blot methods previously described 122). The
frequency of Apo E genotypes for whites in the general population taken from a previous report [23] was compared with
our control popularion.
t tests were used to test for potential differences in quantitative trait levels between groups. x' tests were used for
initial tests of potential differences in Apo E allele and genotype frequencies between groups categorized as demented
versus normal. Regression analysis was used to determine
whether the Apo E genotype was predictive of DRS in the
presence of sex and age effects. This latter analysis was necessary to adjust for the age differences in cases and controls
because Apo E ~4 frequency is known to decline in older
populations 124,251. This raised concerns that an elevated
~4 frequency would not be detected in this population because the cases were older than the controls. In addition,
because men and women may show a different rate of decline
in ~4 frequency as a function of age [26], sex was also included in the regression analysis. The model fit was y = (Y
+ P,a + P1.r + Pig + E , where y = DRS, a = age, s =
sex ( 0 = female, 1 = male), and g = Apo E genotype
(indicated as 1 = f4 present, 0 = ~4 absent), F is random
error. and a , PI. P2, and pi are the regression coefficients.
This analysis was done on actual DRS score, rather than the
recoded affectation status. This increases the power of the
analysis since it does not require artificial dichotomization of
the data. Analyses were also done with g coded as the number
of ~4 alleles.
Discussion
Apo E is well studied because of its role in plasma
cholesterol and triglyceride homeostasis [24]. It mediates the endocytosis of cholesterol, triglyceride, and
phospholipid-rich particles into hepatocytes and other
cells by binding to low-density lipoprotein receptors
and Apo E-specific receptors [24]. Apo E is also involved in the repair response to tissue injury, immuno-
Table. I . Denzogvupbio of-Parkitzsoti's Dikase Putleiits atid Controls
(1)
PD with Normal
Characteristic
Cognition
Number
Age (mean yr)
Sex (male)
Disease duration (mean yr)
Mattis DRS score
Hoehn-Yahr score
UPDRS (total ADL)
UPDRS (total motor)
Blessed DRS
61
67.4 f 7.7
62.30;
6.5 f 5.3
139.5 f 2.6
1.7 f 0.6
9.9 ? 5.1
18.6 t 11.4
0.1 2 0.9
(-3)
(2 I
P D with Dementia
Controls
52
74.7 f
'8
69.9 f 6.5
47.4";
NIA
138.7 ? 3:4
7.6
82.0%
7.2 f 5.4a
107.2 2 19.0
2.7 f 0.0"
17.1 f 7.6
28.0 ? 1 3 . 1
3.5
f
Post Hoc
Comparisons
2>1.3
2 > 1,3
2<1,3
NIA
0.3 f 0.8
0.8 ? 1.8
0.2 f 0.4
3.3
2>1>J
2 > 1 > 3
2 > 1,3
Posr hoc comparisons are Tukey HSD following a significant F at p < 0.01, except for sex. Proportional analyses were used for sex following a significant ~ ' a r p< 0.01.
'Independent tests significant a r p < 0.01.
P D = Parkinson's disease; N/A = not applicable; DRS = Dementia Racing Scale; UPDRS
= activities of daily living; HSD = honestly significant difference (test)
=
Unified Parkinson's Disease Raring Scale; ADL
Koller et al: Apo E Genotypes in PD
243
Table 2. Coinpari.ron of the Distribution of Apolipoprotein E
Genotypes in Parki~t~oni
Disease Patients With and #‘fitbout
Denietitia arid the Control Population
Table 4. RegresJion AnalyJiJ of Demeniia Rating Scale on Age.
Sex, and Apolipoprotein E Genotype
Coefficient
Variable
Estimates
p
a
Constant
Age
192.25
-0.85
- 9.60
-2.59
< 0.0001
PI
P?
PD with
PD with
Dementia
Normal
Cognition
Apo E
Genotypes
(2
212
312
31 3
412
413
414
0
10
62
3
23
2
Apo E
=
Controls
Number
Number
Number
of
of
of
Pi
Patients
Apo E = apolipoprotein E.
c/;
Patients
0
2
12
56
6
23
2
6
38
2
14
1
apolipoprotein E; PD
=
Patients
1
Cf
3 2
1 3 10
59 46
0
0
24 19
1
1
6
29
3
12
1
Parkinson’s disease
Table 1. Contpari.rorz of Apohpoprotrin E Al& Frrquenrir~in
Parkimon’.r Dijease Pu’cltiriits With dnd Without Dementid and
tbe Control Population
~
PD with
PD with
N o r m a l Cognition
i(‘i)
Dementia
Controls
i(7 )
(?i)
8.9
77.5
13.4
~
€2
66
11.5
F3
78.7
73.I
€4
14.8
15.4
Apo E
=
244
Annals of N e u r o l o g y
apolipoprotein; P D
=
Parkinson’s disease
Vol 37
No 2
0.0002
0.0222
0.5276
Strittmatter and colleagues E71 hypothesized that the
lack of ~3 allele may result in disordered microtubular
aggregation and the development of neuronal tangles.
I t has also been suggested that the role of e4 allele is
to exacerbate amyloid deposition in senile plaques
[ 5 , 61.
regulation, and modulation of cell growth and cell differentiation. I t has been identihed in both plaques and
neurtcic tangles { 2 7 ) and binds tightly to P-amyloid (1,
28). Three alleles, e3, ~ 3 and
, e4, arising from single
amino acid substitutions, occur in the general population. T h e most common allele, e3, is present across a
variety of different ethnic groups with a frequency of
approximately 7 5%. [231. Patients homozygous for the
e2 allele may develop type 111 hyperlipidemia. T h e
€4 homozygote patient has elevated cholesterol and
triglyceride levels and is predisposed to coronary artery
disease.
An association between the e4 allele and late-onset
A D is established [ l - 4 , 29-3 I). For the € 4 homozygote, the odds ratio for the risk of A D ranges from 3
to I j (323. Corder and co-workers [41 recently reported that gene dosage affects both risk of A D and
age of onset in the late-onset familial AD. k s k of A D
ranged from 205;’ without an ~4allele to 90%. in the
e4 homozygote. Age of onset ranged from a mean age
of 84.3 years without an e4 to 75.5 years with one ~4
allele and 68.4 years with two e4 copies. Apo E &4/4
A D patients have more senile plaques than e 3 / 3 patients {333. The strong effect of gene dosage suggests
a possible direct biologic link to disease pathogenesis.
Apo E Allele
Sex
Apo E
February 1095
P D like A D is an age-related neurodegenerative disease. T h e etiology of P D is unknown; however, it is
thought that both genetic and environmental influences are important 1341. PD has epidemiologic, clinical, and neuropathologic characteristics similar to AD.
Dementia is common in PD, occurring in up to 4 0 9
of patients 1141. Several pathologic substrates appear
to be responsible for dementia in PD, i.e., coincident
A D (neuritic plaques and neurofibrillary tangles), Lewy
bodies (in cortical and subcortical structures), and primary nigral degeneration El?, 18, 35, 363. Thus it is
possible that an Apo E allele could be a risk factor
either for P D o r P D with dementia. However, our data
indicate that Apo E is not a susceptibility gene or risk
factor in PD, even when age and sex are accounted for
in the analysis. Marder and co-workers {377 also found
no difference in Apo E e4 allele frequency in 22 P D
patients with dementia, 57 PD patients without dementia, and 44 nondemented controls. These results
suggest that amyloid deposition observed in nonneuritic plaques of PD and the neurohbrillary changes reported in PD dementia are not related to a mechanism
associated with Apo E. T h e dementia of P D most likely
has a differenc mechanism than AD. Thal and associates [ 381 in a preliminary report of pathologically confirmed cases concluded that Apo E ~4 allele is overrepresented in A D and the Lewy body variant of A D
( A D pathology and Lewy bodies) but not in diffuse
Lewy body disease (DLBD). T h e entity of DLBD may
be more related to PD and AD.
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245
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