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The 5-HTTPR*S/*L Polymorphism and Aggressive Behavior in Alzheimer Disease
Danielle L. Sukonick, BA;
Bruce G. Pollock, MD, PhD;
Robert A. Sweet, MD;
Benoit H. Mulsant, MD;
Jules Rosen, MD;
William E. Klunk, MD, PhD;
Kari B. Kastango, MS;
Steven T. DeKosky, MD;
Robert E. Ferrell, PhD
Arch Neurol. 2001;58:1425-1428.
ABSTRACT
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Background Aggressive behavior in Alzheimer disease (AD) has been linked to dysfunction
of serotonin neurotransmission. Homozygosity for the long variant (*L) of an identified biallelic polymorphism of the serotonin transporter
promoter region (5-HTTPR) is associated with increased expression of the transporter
protein and increased speed of response to serotonin reuptake inhibitor treatment.
Objective To determine whether the *L/*L genotype and
the *L allele are associated with an increased risk
of aggressive symptoms in patients with AD.
Design Case-control study.
Setting University hospital geriatric psychiatry inpatient program and Alzheimer
disease research center.
Subjects Fifty-eight patients with AD with a history of aggressive behavior and
79 never-aggressive patients with AD with comparable severity of cognitive
impairment.
Main Outcome Measures The 5-HTTPR genotype and allele frequency.
Results The *L/*L genotype was significantly associated
with aggression in patients with AD (odds ratio, 2.8; 95% confidence interval,
1.2-6.5). Similar results were obtained for *L allele
frequency.
Conclusion The 5-HTTPR*L allele and *L/*L genotype may predispose patients with AD to develop aggressive
behavior.
INTRODUCTION
ALZHEIMER disease (AD) is frequently complicated by psychiatric symptoms
including verbal and physical aggression.1
Altered function of the serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter
system has been implicated in impulsive aggressive behavior2, 3
and in aggressive behavior in patients diagnosed as having AD.4, 5, 6, 7
Postmortem and biopsy studies of brains from patients with AD show a decrease
in levels of 5-HT, 5-HT receptors, and the 5-HT transporter (5-HTT).8, 9, 10 The concentration of
5-hydroxyindoleacetic acid, a metabolite of 5-HT, has been shown to be decreased
in the cerebrospinal fluid and cerebral cortex of patients with AD.4, 11 A few studies have demonstrated a
specific association between aggressive behavior in AD and greatly diminished
cortical levels of 5-HT.4, 5 Therapeutic
agents that act on the 5-HT system have been shown to be helpful in the treatment
of aggression in patients diagnosed as having AD.12, 13, 14
Consistent with the findings of excess 5-HT loss in aggressive subjects with
AD, fenfluramine challenge studies have found a hypersensitive postsynaptic
response in agitated subjects with AD compared with nonagitated control subjects
with AD.6, 15
In 1996, a 44–base pair (bp) insertion/deletion polymorphism (5HTTPR) was discovered in the 5' promoter region
of the 5-HTT gene (HTT, SLC6A4).16
The 5HTTPR alleles are defined by differing numbers
of a 44-bp GC-rich repetitive sequence. The basal transcriptional activity
of the long variant (*L) is about 2.5- to 3-fold
higher than that of the short variant (*S).16, 17 This differential rate of transcription
results in a reduction of 5-HT reuptake sites of approximately 40% in *S/*S homozygotes and a reduction of approximately 30%
for heterozygotes (*S/*L), leading some to suggest
that the *S allele is functionally dominant.18
We hypothesized that the *L/*L genotype would
lead to a depletion of extraneuronal 5-HT and might contribute to the risk
of aggression in AD. We examined this hypothesis in 137 subjects diagnosed
as having possible or probable AD, 58 of whom demonstrated aggressive behavior.
PATIENTS AND METHODS
PATIENTS
All patients were examined at the Geriatric Psychiatry Inpatient Program
and the Alzheimer Disease Research Center of the University of Pittsburgh
Medical Center, Pittsburgh, Pa, between December 5, 1991, and October 13,
1999. Subjects underwent an extensive diagnostic and behavioral assessment,
which has been described in detail elsewhere,19, 20, 21, 22
and received a diagnosis of possible or probable AD by means of the criteria
of the National Institute of Neurologic and Communicative Disorders and Stroke–Alzheimer
Disease and Related Disorders Association.23
Aggressive subjects, as defined by the presence
of physical or verbal aggression rated with the Empirical Behavioral Pathology
in Alzheimer Disease scale,24 were identified
among participants in a clinical trial for treatment of behavioral disturbances
in dementia conducted at the Geriatric Psychiatry Inpatient Program. Because
of evidence that frequency of aggression in patients with AD may increase
with severity of dementia,25 a group of never-aggressive
patients with AD, with similar dementia severity as rated on the Mini-Mental
State Examination(MMSE),26 was also identified
from subjects participating in the Alzheimer Disease Research Center. Never aggressive was defined as the absence, on initial
and annual follow-up examinations, of verbal and physical aggression as defined
by the Behavior Rating Scale for Dementia of the Consortium to Establish a
Registry for Alzheimer Disease.1 All data collected
in this study were obtained with protocols approved by the Institutional Review
Board of the University of Pittsburgh.
GENOTYPING
Lymphocytes were harvested from whole blood and DNA was extracted from
lymphocytes by means of a DNA blood kit (QIAamp; Qiagen Inc, Valencia, Calif).
The *S and *L alleles were
determined by using DNA amplification (polymerase chain reaction) and establishing
flanking primers. Amplification products were resolved by electrophoresis
and visualized with ethidium bromide staining and UV transillumination, according
to the method of Edenberg and Reynolds.15 Samples
from all 137 patients were analyzed for the 5-HTTPR*S/*L polymorphism.
STATISTICAL ANALYSIS
Pearson  2 test (exact method) was used to compare the
groups with respect to race, sex, and allele and genotype frequencies (StatXact4,
version 4.0.1; Cytel Software Corp, Cambridge, Mass). Intergroup differences
in age and MSSE score were assessed by t tests (SAS,
version 8.0; SAS Institute Inc, Cary, NC). Equality of variance was assessed
before the t tests were performed. All tests were
2-tailed, and a significance level of .05 was used.
RESULTS
Demographic and clinical characteristics of patients with AD exhibiting
aggressive behavior (n = 58) and those with no history of aggressive behavior
(n = 79) are shown in Table 1.
There were no significant differences with regard to sex and race. The MMSE
scores also did not differ between groups, confirming adequate matching on
this variable. Mean age was significantly higher, however, in the aggressive
subjects (t = 4.3, P<.001).
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Table 1. Demographic and Clinical Data for Aggressive and Never-Aggressive
Patients With Alzheimer Disease
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Genotype and allele frequencies of the 5HTTPR
polymorphism among aggressive and never-aggressive patients with AD are shown
in Table 2. The increased frequency
of *L alleles in the aggressive patients was highly
significant (21 = 18.0, P<.001).
There was a corresponding significant difference in genotype distribution
between the aggressive and never-aggressive patients (21 = 7.1, P<.01). Aggressive patients with
AD had a significantly higher frequency of *L/*L
genotypes than the never-aggressive patients with AD. The odds ratio (95%
confidence interval) for aggression associated with the *L/*L genotype was 2.8 (1.2-6.5). When genotype, age, sex, and MMSE
score were entered into a stepwise logistic regression model with aggression
as the dependent variable, both *L/*L genotype and
age, but not sex or MMSE, demonstrated significant associations with aggression
(genotype: 21 = 6.2, P
= .01; age: 21 = 15.8, P<.001).
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Table 2. Genotype and Allele Frequency Data for Aggressive and Never-Aggressive
Patients With Alzheimer Disease
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COMMENT
To our knowledge, this is the first study to relate aggressive behavior
in AD to the 5-HTTPR polymorphism. As hypothesized, there was a significantly
greater frequency of the *L/*L genotype in the aggressive
subjects. We also found aggressive patients with AD to have a significantly
higher frequency of *L alleles than never-aggressive
patients with AD.
We predicted that the *L/*L genotype would
be more commonly found in patients with AD with aggressive behavior because
of the established relationship between 5-HT depletion and aggression.2, 3, 4, 5, 6, 7
There is reason to believe that subjects who are of the *L/*L genotype would have less 5-HT available at the synapse because
of the higher density of 5-HTT that this genotype confers.16, 17
The low level of synaptic 5-HT caused by increased reuptake would therefore
approximate the reduced 5-HT levels seen in subjects with impulsive aggressive
behavior associated with other neuropsychiatric conditions,2, 3, 27
and in aggressive patients with AD.4, 5
While reports of increased prolactin response to fenfluramine challenge in
agitated patients with AD may initially seem to contradict these findings,
they may be readily understood as an up-regulated postsynaptic state that
develops in response to tonically reduced intrasynaptic 5-HT.
In addition to the hypothesized association of aggression with the *L/*L genotype, we found a significant elevation of *L allele frequency. Inspection of the rates of aggression
in the genotype groups in Table 2
shows a progressive increase in aggression frequency from *S/*S to *S/*L to *L/*L subjects: aggression was present in 1 of 27 *S/*S subjects, 34 of 72 *S/*L subjects, and 23
of 38 *L/*L subjects. This pattern is not consistent
with reports of *S allele dominance.18, 28
The relationship between 5HTTPR genotype and 5-HTT
expression in regions of human brain29, 30
may differ, however, from that observed in in vitro expression systems or
in peripheral tissues. In fact the 5-HTT promoter region is subject to regulation
by multiple transcription factors31; thus,
the effect of the *L and *S
alleles on 5-HTT expression may vary in accordance with the specific transcription
factors expressed in a specific tissue, region of tissue, or disease state.
It is worth noting that, in some previous studies that found an association
of 5HTTPR genotype with AD risk, a pattern like that
of the current study, ie, more consistent with codominance than with a dominant-recessive
system, has been observed.32, 33
The preclinical neurochemical findings of reduced 5-HT levels in aggressive
patients with AD have suggested a role for 5-HT–enhancing drugs in the
treatment of aggressive behaviors in AD. Emerging clinical data suggest this
may indeed be the case.12, 13, 34
The current genetic findings are consistent with these earlier observations.
Moreover, we previously reported that, among older subjects treated for major
depressive illness with the selective 5-HT reuptake inhibitor paroxetine, *L/*L subjects had a significantly earlier antidepressant
response than their *S/*S and *S/*L counterparts.35 It remains to
be determined whether the *L/*L genotype will similarly
predict response of aggressive behaviors in AD to treatment with 5-HT reuptake
inhibitors.
Previous research on the 5HTTPR polymorphism
and AD found an association between the *S allele
and the development of late-onset AD in European and Brazilian subjects,32, 33, 36 although a subsequent
study failed to replicate this association.37
Our findings suggest that these inconsistent associations could result from
variability in the extent to which aggressive patients with AD were included.
Behavioral characterization of subjects should be considered in future 5-HTTPR
research in patients with AD.
Because this is the first study relating aggression in patients with
AD to the 5-HTTPR polymorphism, independent replication will be necessary
to confirm the association of the *L allele with
aggressive behavioral disturbance. The major potential limitation of the study
is the differing referral sources for aggressive subjects (Geriatric Psychiatry
Inpatient Program) and nonaggressive subjects (Alzheimer Disease Research
Center), also rated by different behavioral measures (Empirical Behavioral
Pathology in Alzheimer Disease and Behavior Rating Scale, respectively). If
referral source is a surrogate for a subject characteristic (other than aggression)
that was associated with the 5HTTPR, a false-positive
association with aggression could have resulted. The current study was also
limited by incomplete matching for subject age, with the aggressive AD group
being 6 years older on average than the never-aggressive group. Nevertheless,
the association of genotype with aggression remained significant after controlling
for the effect of age. Finally, as in all genetic association studies, a type
I error might result from population stratification effects.
In summary, we found the *L allele and the *L/*L genotype of the 5HTTPR polymorphism
to be increased in frequency in aggressive patients with AD when compared
with patients with AD who were never aggressive. This study is the first of
its kind, to our knowledge, and therefore must be considered preliminary,
pending independent replication. Future studies examining the association
between 5-TTPR genotype and response to serotonergic
treatment of aggression in AD are also warranted.
AUTHOR INFORMATION
Accepted for publication March 26, 2001.
This study was supported in part by research grants MH01509, MH59666,
MH52247, and MH01613 from the National Institute of Mental Health and AG05133
from the National Institute on Aging, Bethesda, Md, and by the John F. and
Nancy A. Emmerling Fund of The Pittsburgh Foundation, Pittsburgh, Pa.
We gratefully acknowledge the efforts of the research staff of the Alzheimer
Disease Research Center and the Geriatric Psychopharmacology Program at the
University of Pittsburgh. We would like to acknowledge the assistance of Lorri
Mulkerin with the preparation of the manuscript.
From the Division of Geriatrics and Neuropsychiatry, Department of
Psychiatry (Mss Sukonick and Kastango and Drs Pollock, Sweet, Mulsant, Rosen,
Klunk, and DeKosky), Department of Neurology, School of Medicine (Dr DeKosky),
and Department of Human Genetics, Graduate School of Public Health (Dr Ferrell),
University of Pittsburgh, Pittsburgh, Pa; and the Geriatric Research, Education,
and Clinical Center, Veterans Affairs Pittsburgh Health Care System (Dr Mulsant).
Dr Mulsant has received grant or research support from the National Institute
of Mental Health, AstraZeneca, Inc, Janssen Pharmaceutica, Pfizer, Inc/Eisai
Pharmaceuticals, and GlaxoSmithKline; is a consultant to AstraZeneca, Inc,
Eli Lilly and Company, Janssen Pharmaceutica, Pfizer, Inc, and GlaxoSmithKline;
is on the speaker's bureau for AstraZeneca, Inc, Janssen Pharmaceutica, Pfizer,
Inc/Eisai Pharmaceuticals, Searle, and GlaxoSmithKline; owns stock in Akzo-Nobel,
Biogen, Inc, Celsion Corporation, Elan Corporation, Forest Laboratories, Inc,
and Immune Response Corporation; is a major stock holder in Biogen, Inc; and
has received honoraria from AstraZeneca, Inc, Eli Lilly and Company, Janssen
Pharmaceutica, Pfizer, Inc/Eisai Pharmaceuticals, Organon, Searle, and GlaxoSmithKline.
Corresponding author and reprints: Robert A. Sweet, MD, Western Psychiatric
Institute and Clinic, 3811 O'Hara St, Pittsburgh, PA 15213 (e-mail:
SweetRA{at}MSX.UPMC.EDU).
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