Lack of Effect of Apolipoprotein E E4 Allele on Neuropsychiatric Manifestations in Alzheimer's Disease
Publication: The Journal of Neuropsychiatry and Clinical Neurosciences
Abstract
The association between the apolipoprotein E epsilon 4 (APOE E4) allele and a wide spectrum of behavioral symptoms of Alzheimer's disease (AD) was investigated. Neither the severity nor the presence of any behavioral changes was associated with the number of APOE E4 alleles, even after controlling for the effects of age at onset, sex, education level, duration of illness, and severity of dementia. The findings do not support the hypothesis that neuropsychiatric manifestations of AD are different in patients with the APOE E4 allele.
Behavioral changes are common in patients with Alzheimer's disease (AD) and have a major impact on their quality of life and social affiliations.1,2 The underlying mechanism for these behavioral symptoms in AD is not well understood. The apolipoprotein E epsilon 4 (APOE E4) allele is a known risk factor in late-onset AD. The APOE E4 allele has been assumed to be involved in the pathomechanism of AD, and thus the association between the E4 allele and the clinical expression, including psychiatric manifestations, of AD has been hypothesized. Several studies have examined the involvement of this allele in common mental symptoms, including delusions, hallucinations, and depression, with conflicting results.3–9 Some of these conflicts may be accounted for by methodological factors, including different definitions of behavioral changes, the lack of statistical power with small sample sizes, and inappropriate application of statistical analysis without controlling the possible confounding factors. In the present study, taking these concerns into consideration, we analyzed the relationship between the APOE E4 allele and neuropsychiatric manifestations in a considerably large cohort by using a well-established comprehensive tool for the assessment of behavioral abnormalities.
METHODS
Subjects
All procedures of this study strictly followed the Clinical Study Guidelines of the Ethics Committee of Hyogo Institute for Aging Brain and Cognitive Disorders (HI-ABCD), Himeji, Japan, in 1993, and were approved by the Internal Review Board. After a complete description of all procedures of this study, written informed consent was obtained from patients or their relatives.
The subjects of this study were 175 of a consecutive series of 279 Japanese patients with sporadic AD who were given a short-term admission to the infirmary of the HI-ABCD, a research-oriented hospital for dementia, for examination between August 1995 and September 1997. All patients were examined by both neurologists and psychiatrists and were given routine laboratory tests and standard neuropsychological examinations. In addition, electroencephalography, magnetic resonance (MR) imaging of the brain, MR angiography of the neck and head, and cerebral perfusion/metabolism studies by positron emission tomography or single-photon emission computed tomography were done. All results were incorporated in the diagnosis. The inclusion criteria were those of both the DSM-IV10 for dementia of the Alzheimer's type and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association11 for probable AD. One hundred four patients were excluded from this study in accordance with established exclusion criteria. These consisted of complications of other neurological diseases (n=33) or physical illnesses (n=12), evidence of parkinsonism (n=6) or focal brain lesions on MRI (n=3), the presence of severe hearing or vision impairments (n=2), a history of mental illness or substance abuse before the onset of dementia (n=8), the absence of reliable informants (n=28) such as living-with family or caregivers, or the inability to obtain informed consent (n=12).
The included patients were 146 women and 29 men; the age at examination (mean±SD) was 71.9±8.1 years, and the mean educational attainment was 9.3±2.5 years. The functional severity was 0.5 (very mild) in 20 patients, 1 (mild) in 100 patients, 2 (moderate) in 43 patients, and 3 (severe) in 12 patients as determined by the Clinical Dementia Rating Scale (CDR).12 The age at onset and the duration of the disease were ascertained through an interview with the primary caregiver. Age at onset was defined as the age of the first appearance of symptoms of sufficient severity to interfere with social or occupational functioning, and the duration was defined as the time in months between the onset and the admission.13 The mean age at symptom onset and duration of symptoms were 69.1±8.5 years and 33.6±20.7 months, respectively. The mean value of the Mini-Mental State Examination14 was 19.3±4.6.
Assessment of Psychiatric Status
We assessed each patient's behavioral changes semiquantitatively during an interview with the caregiver by using the Japanese version15 of the Neuropsychiatric Inventory (NPI).16 Satisfactory reliability and validity have been established for the Japanese version.15 A single physician was employed in the assessment. In the NPI, the following 10 behavioral and psychotic changes in dementia were rated on the basis of the patient's condition in the previous month before the interview: delusions, hallucinations, depression (dysphoria), anxiety, agitation and aggression, disinhibition, euphoria, irritability and lability, apathy, and aberrant motor activity. According to the defined criteria, the severity of each manifestation was classified into 3 grades (from 1 to 3) and frequency of each manifestation was classified into 4 grades (from 1 to 4). The NPI score (severity×frequency) was calculated for each manifestation. Behavioral changes were also rated on a present/absent basis.
Determination of APOE Genotype
The detailed method for APOE genotyping is described elsewhere.17 In brief, genomic DNA was extracted from whole blood samples by the phenolchloroform method and was amplified by the polymerase chain reaction (PCR) as described by Wenham et al.18 The PCR products were digested with 10 units of Hha I for 5 hours at 37° C. The DNA fragments were electrophoresed for 5 hours at 60 mA through a 15% nondenaturing polyacrylamide gel. The gel was stained with ethidium bromide and photographed under ultraviolet light. The genotypes were determined by the size of DNA fragments.
Statistical Analysis
Because a dose effect of the APOE E4 alleles has been shown to affect AD risk,19–21 we tested the relationship between the number of E4 alleles and the NPI score of each behavioral change. We used Spearman rank correlation coefficients because the NPI scores were not normally distributed. To examine the effects of E4 alleles on the presence of each behavioral change, we also used a multiple logistic analysis, with the dichotomy (presence or absence) of each manifestation as a dependent variable and the number of E4 alleles as an independent variable. Each analysis was repeated initially without controlling the effect of potential confounding variables, and secondarily by enrolling age at onset, sex, duration of symptoms, education level, and CDR as severity of dementia into the model. In order to reduce the chance of a statistical type II error, we adopted a nonconservative alpha level of 0.05 despite the use of multiple comparisons.
RESULTS
The APOE genotyping was E2/E3 in 6 patients, E2/E4 in 2 patients, E3/E3 in 61 patients, E3/E4 in 88 patients, and E4/E4 in 18 patients. Thus, 67 patients had no E4 allele, 90 had one E4 allele, and 18 had two E4 alleles. The frequency and the mean value for the NPI score of each neuropsychiatric manifestation are summarized in Table 1. The most common abnormal behavioral manifestation was apathy, followed by aberrant motor behavior, delusions, dysphoria, and irritability. The least common was euphoria.
The correlation analysis between the number of APOE E4 alleles and each NPI score revealed no significant association (Table 2). Even after the effects of age at onset, sex, duration of disease, education level, and CDR severity of dementia were controlled, the results remain unchanged. The multiple logistic regression analysis (Table 3) also failed to show any association between the number of APOE E4 alleles and the presence of any behavioral changes, either before or after controlling the possible confounding factors. For euphoria, controlling these factors was not possible because the frequency of positive cases was too low.
DISCUSSION
The NPI results obtained from the Japanese AD patients demonstrated that apathy was the most common symptom and that disinhibition, hallucinations, and euphoria were rare. This finding is consistent with the findings of other studies in the United States, Italy, and Mexico.22 Anxiety and agitation in our subjects were not uncommon, but they were one-third less frequent than they were in the United States.2,22 On the other hand, the distribution of the APOE genotype demonstrated in this study was similar to the distributions reported in other races and countries.17,23
The major finding in the present study is that the number of APOE E4 alleles was not associated with any of the behavioral changes in Japanese probable AD patients in terms of prevalence or severity. Ramachandran et al.3 reported an association of the APOE E4 allele with psychosis and depression. Murphy et al.4 reported that the APOE E4 allele is associated with greater behavioral disturbances in AD patients. However, they did not investigate individual behavioral symptoms. On the other hand, studies that have analyzed the effect of the APOE E4 allele on delusions, hallucinations, and depression in larger cohorts while controlling confounding factors failed to demonstrate the association of the APOE E4 allele with either delusions,5–8 hallucinations,5–9 or depression.5–7,9 Together with these earlier studies, the present study clearly demonstrated that the APOE E4 allele has no effect on the manifestation of delusions, hallucinations, or depression in AD. Although AD patients manifest other types of behavioral changes, few studies have addressed the effect of the APOE E4 allele. Our results demonstrated no effect of APOE E4 alleles on any symptoms including agitation, anxiety, euphoria, apathy, disinhibition, irritability, or aberrant motor behavior, and are consistent with a study of Holmes et al.7 that reported no significant association with noncognitive symptoms including aggression, wandering, and stereotyped behaviors. We confirmed in the Japanese patients that the neuropsychiatric manifestation in AD is not associated with the APOE genotype.
The APOE E4 allele did not associate with behavioral changes in AD. The APOE E4 allele is an important risk factor for developing AD and may affect the pathological changes.23,24 However, previous epidemiological studies have indicated that the profile and rate of cognitive impairment7,25–29 and survival rates30,31 are not different according to the APOE genotype once persons have a diagnosis of AD. Moreover, cerebral glucose metabolism studies did not find any APOE genotype–related differences in patients with the full dementia syndrome of AD.32,33 Our findings are compatible with these studies and do not support the hypothesis that neuropsychiatric manifestation of AD is different in patients with the APOE E4 allele.
ACKNOWLEDGMENTS
The authors thank Hajime Kitagaki, M.D., and Kazunari Ishii, M.D., of the Division of Neuroimaging Research, for their help in various parts of the study, and Yoko Takatsuki, B.A., R.S.T., and Akitsugu Tokimasa, R.O.T., of the Neurorehabilitation Service, for their technical assistance.
References
1.
Cummings JL, Victoroff JI: Noncognitive neuropsychiatric syndromes in Alzheimer's disease. Neuropsychiatry Neuropsychol Behav Neurol 1990; 3:140–158
2.
Mega MS, Cummings JL, Fiorello T, et al: The spectrum of behavioral changes in Alzheimer's disease. Neurology 1996; 46:130–135
3.
Ramachandran G, Marder K, Tang M, et al: A preliminary study of apolipoprotein E genotype and psychiatric manifestations of Alzheimer's disease. Neurology 1996; 47:256–259
4.
Murphy GM Jr, Taylor J, Tinklenberg JR, et al: The apolipoprotein E ε4 allele is associated with increased behavioral disturbance in Alzheimer's disease. Am J Geriatr Psychiatry 1997; 5:88–89
5.
Lyketsos CG, Baker L, Warren A, et al: Depression, delusions, and hallucinations in Alzheimer's disease: no relationship to apolipoprotein E genotype. J Neuropsychiatry Clin Neurosci 1997; 9:64–67
6.
Lopez OL, Kamboh MI, Becker JT, et al: The apolipoprotein E ε4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease. Neurology 1997; 49:794–797
7.
Holmes C, Levy R, McLoughlin DM, et al: Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry 1996; 61:580–583
8.
Hirono N, Mori E, Yasuda M, et al: Factors associated with psychotic symptoms in Alzheimer's disease. J Neurol Neurosurg Psychiatry 1998; 64:648–652
9.
Cantillon M, Harwood D, Barker W, et al: No association between apolipoprotein E genotype and late-onset depression in Alzheimer's disease. Biol Psychiatry 1997; 41:246–248
10.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC, American Psychiatric Association, 1994
11.
McKhann G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984; 34:939–944
12.
Hughes CP, Berg L, Danziger WL, et al: A new clinical scale for the staging of dementia. Br J Psychiatry 1982; 140:566–572
13.
Sano M, Devanand DP, Richards M, et al: A standardized technique for establishing onset and duration of symptoms of Alzheimer's disease. Arch Neurol 1995; 52: 961–966
14.
Folstein MF, Folstein SE, McHugh PR: “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189–198
15.
Hirono N, Mori E, Ikejiri Y, et al: [Japanese version of the Neuropsychiatric Inventory: a scoring system for neuropsychiatric disturbances in dementia patients] (Japanese). No to Shinkei 1997; 49:266–271
16.
Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308–2314
17.
Yasuda M, Maeda K, Shimada K, et al: Apolipoprotein E ε4 allele and gender difference in risk of Alzheimer's disease. Alzheimer's Research 1995; 1:77–81
18.
Wenham PR, Price WH, Blandell G: Apolipoprotein E genotyping by one-stage PCR. Lancet 1991; 337:1158–1159
19.
Corder EH, Saunders AM, Strittmatter WJ, et al: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261:921–923
20.
Poirier J, Davignon J, Bouthillier D, et al: Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 1993; 342:697–699
21.
Lucotte G, Turpin JC, Landais P: Apolipoprotein E-ε4 allele doses in late-onset Alzheimer's disease. Ann Neurol 1994; 36:681–682
22.
Cummings JL: The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997; 48(suppl 6):S10–S16
23.
Levy-Lahad E, Bird TD: Genetic factors in Alzheimer's disease: a review of recent advances. Ann Neurol 1996; 40:829–840
24.
Yasuda M, Mori E, Kitagaki H, et al: Apolipoprotein E ε4 allele and whole brain atrophy in late-onset Alzheimer's disease. Am J Psychiatry 1998; 155:779–784
25.
Basun H, Grut M, Winblad B, et al: Apolipoprotein ε4 allele and disease progression in patients with late-onset Alzheimer's disease. Neurosci Lett 1995; 183:32–34
26.
Dal Forno G, Rasmusson X, Brandt J, et al: Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease. Arch Neurol 1996; 53:345–350
27.
Kurz A, Egensperger R, Haupt M, et al: Apolipoprotein E ε4 allele, cognitive decline, and deterioration of everyday performance in Alzheimer's disease. Neurology 1996; 47:440–443
28.
Growdon JH, Locascio JJ, Corkin S, et al: Apolipoprotein E genotype does not influence rates of cognitive decline in Alzheimer's disease. Neurology 1996; 47:444–448
29.
Murphy GM Jr, Taylor J, Kraemer HC, et al: No association between apolipoprotein E ε4 allele and rate of decline in Alzheimer's disease. Am J Psychiatry 1997; 154:603–608
30.
Corder EH, Saunders AM, Strittmatter WJ, et al: Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risks of death and Alzheimer's disease. Neurology 1995; 45:1323–1328
31.
Norrman J, Brookes AJ, Yates C, et al: Apolipoprotein E genotype and its effect on duration and severity of early and late onset Alzheimer's disease. Br J Psychiatry 1995; 167:533–536
32.
Corder EH, Jelic V, Basun H, et al: No difference in cerebral glucose metabolism in patients with Alzheimer disease and differing apolipoprotein E genotypes. Arch Neurol 1997; 54:273–277
33.
Hirono N, Mori E, Yasuda M, et al: Lack of association of apolipoprotein E ε4 allele dose with cerebral glucose metabolism in Alzheimer's disease. Alzheimer Dis Assoc Disord (in press)
Information & Authors
Information
Published In
History
Published online: 1 February 1999
Published in print: February 1999
Authors
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
There are no citations for this item
View Options
View options
PDF/ePub
View PDF/ePubGet Access
Login options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).