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Clinical and Research Reports   |    
Neuropsychiatric Associations of Apolipoprotein E Alleles in Subjects With Combat-Related Posttraumatic Stress Disorder
Thomas Freeman, M.D.; Vincent Roca, Ph.D.; Fred Guggenheim, M.D.; Tim Kimbrell, M.D.; W.S.T. Griffin, Ph.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2005;17:541-543. doi:10.1176/appi.neuropsych.17.4.541
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Received April 19, 2004; revised June 22, 2004; accepted June 25, 2004. From the Mental Health Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; South Central MIRECC; University of Arkansas Medical Sciences Department of Psychiatry, Little Rock, Arkansas; University of Arkansas Medical Sciences Department of Geriatrics, Little Rock, Arkansas; Geriatric, Research, Education, and Clinical Centers; Donald W. Reynolds Center on Aging. Address correspondence to Dr. Freeman, North Little Rock PTSD Program, North Little Rock VAMC, Mail Code: 116AP/NLR, 2200 Fort Roots Dr., North Little Rock, AR 72114; THOMAS.FREEMAN@MED.VA.GOV (E-mail).

Abstract

Previous studies have reported associations between apolipoprotein E (APOE) genotype, cognitive function, and psychopathology in psychiatric populations. The authors investigated the associations between APOE allele status, memory function, and posttraumatic stress disorder (PTSD) symptom severity in PTSD subjects. Presence of the APOE 2 allele was associated with significantly worse reexperiencing symptoms and impaired memory function in this population.

Abstract Teaser
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Apolipoprotein E (APOE) is a 34 kDa protein that mediates the binding of lipoproteins to the low density lipoprotein receptor. The three common isoforms of human APOE differ at two amino acid positions, 112, and 158. The E4 isoform of the apolipoprotein E allele (APOE) has been linked to a number of neuropsychiatric illnesses, primarily Alzheimer’s disease (AD), but also with stress and depression in geriatric populations.1 The presence of the APOE4 allele has also been associated with increased rates of hippocampal volume loss.2 The APOE2 allele has been claimed to confer a protective effect to AD.3 Although distribution of APOE alleles and relationships of APOE alleles to neuropsychiatric symptoms have not been previously studied in subjects with PTSD, certain rationales support this investigation. The APOE 4 allele has been associated with impairments in subjective and objective memory,4 as well as smaller hippocampal volumes.5 Individuals with chronic PTSD have been shown to exhibit more impaired memory, attentional deficits, more limited executive functions,6 and smaller hippocampal volumes7 than comparison populations. Because of the associations between hippocampal morphometry, memory, and APOE genotype in other populations, we felt that further investigation in PTSD subjects was warranted.

Given the previous associations between psychological symptoms and other genetic markers in PTSD subjects, we sought to determine if PTSD specific symptoms had any relationship to APOE status. We hypothesized that the presence of the APOE4 allele might be associated with more PTSD-related impairments, given similar associations in other psychiatric illnesses.

Data came from 54 Caucasian male veterans with combat-related posttraumatic stress disorder (PTSD) admitted consecutively to the Central Arkansas Veterans Health care System’s (CAVHS) residential PTSD treatment program. The research protocol was approved by the Human Use Committee of the University of Arkansas for Medical Sciences, and written informed consent was obtained from all subjects. All subjects were assessed using the Clinician Administered PTSD Scale (CAPS-2)8 and the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (SCID).9 APOE genotype was assessed from buccal cell samples using standard techniques10 by personnel blinded to subject diagnostic status and symptom severity. A portion of the sample-33 of the 54 subjects-also completed memory testing with the Weschler Memory Scale-Third Edition (WMS-III),11 and completed testing with the Wisconsin Card Sorting Test (WCST).12

Average age for all subjects was 53 (SD=5.9) years. Average years of education for the sample was 11.7 (SD=2.6) years. Average total CAPS-2 score for the group was 97.3 (SD=17.9), average CAPS-2 subscale scores were as follows: CAPS-2 reexperiencing-24.3 (SD=7.4) CAPS-2 avoidance-40.1 (SD=8.7), CAPS-2 arousal-32.7 (SD=5.2). Distribution of the APOE genotype was as follows: 2/2—16.7%, 2/3—3.7%, 2/4—5.6%, 3/3—44.4%, 3/4—29.4%, 4/4—0%. In addition to meeting criteria for PTSD, 81.5% of the sample met SCID lifetime or current criteria for either major depression or dysthymic disorder, 18.5% of the sample met criteria for panic disorder, 64.8% met criteria for lifetime alcohol abuse or dependence, and 13% met criteria for lifetime substance abuse or dependence. Due to the relatively small number of subjects, we initially tested our hypothesis by comparing subjects with one APOE4 allele (2/4, 3/4) to all other subjects. No significant differences in PTSD symptoms or memory were noted between groups. However, when a comparison was made between subjects with at least one APOE2 allele (2/2, 2/3, 2/4; N=14) and the remainder of the sample (N=40), those subjects with the APOE2 allele had significantly higher CAPS-2 reexperiencing scores (29.7 , compared to 22.4 ; t=3.49, p=0.001, two-tailed t test) than the remainder of the study sample, but did not differ from the remainder of the sample in terms of avoidance or arousal symptom clusters. When comparisons were made between groups given neuropsychological testing (N=33), those subjects with at least one APOE2 allele (N=9) performed significantly poorer on several of the WMS-III’s Immediate Memory scales (Logical Memory (LM): (5.5 [SD=1.1] compared to 9.5 [SD=2.9]; t=−3.69, p<0.001; Family Pictures [FP]: 6.82, SD=2.41 compared to 9.71, SD=2.22; t=−2.93, p=0.007) than the remainder of the sample, but did not differ on any of the WCST measures. In the subject sample with at least one APOE2 allele, more elevated CAPS-2 reexperiencing symptoms correlated significantly with lower FP scores (r=−0.859, p=0.013), though not with lower LM scores.

Rather than finding an association between the APOE4 allele and impaired function in this population, we found an association between possession of the APOE2 allele, more impaired memory function, and more significant reexperiencing symptoms in this group of chronic, combat-related PTSD subjects. Given the limited size of our sample and a subject population with such high levels of psychiatric comorbidity as this, these findings can be preliminary at best, but do suggest the need to further investigate the association between APOE genotype and neuropsychiatric function in this population. The isolated relationship of reexperiencing symptoms—the PTSD symptom cluster most clearly associated with memory—and impaired WMS-III scores in subjects with the APOE2 genotype suggests more significant disruptions of memory systems in these individuals.

A speculative mechanism by which APOE2 may confer impaired memory function and worsening reexperiencing symptoms would implicate the hypothalamic-pituitary-adrenal (HPA) axis and aberrant hippocampal function. Peskind and colleagues have reported that the APOE2 genotype is associated with lower cortisol in Alzheimer’s subjects and healthy controls.13 Low cortisol has been frequently reported in chronic, combat-related PTSD14 and there is evidence that low cortisol is associated with decreased hippocampal neuronal integrity.15 Further study in larger populations with the addition of neuroimaging techniques to study hippocampal structure and biochemistry in relationship to APOE genotype appears warranted.

Gallagher-Thompson D, O’Hara R, Simmons A: Apolipoprotein E epsilon4 allele affects the relationship between stress and depression in caregivers of patients with Alzheimer’s disease. J Geriatr Psychiatry Neurol  2001; 14:115—119
[CrossRef] | [PubMed]
 
Cohen RM, Small C, Lalonde F: Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women. Neurology  2001; 57:2223—2228
[PubMed]
 
Lippa CF, Smith TW, Saunders WB: Apolipoprotein E-epsilon 2 and Alzheimer’s disease: genotype influences pathologic phenotype. Neurology  1997; 48:515—519
[PubMed]
 
Flory JD, Manuck SB, Ferrell RE: Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. Am J Med Genet  2000; 96:707—711
[CrossRef] | [PubMed]
 
Kuller LH, Shemanski L, Manolio T: Relationship between APOE, MRI findings, and cognitive function in the Cardiovascular Health Study. Stroke  1998; 29:388—398
[CrossRef] | [PubMed]
 
Golier J, Yehuda R: Neuropsychological processes in post-traumatic stress disorder. Psychiatr Clin North Am  2002; 25:295—315
[CrossRef] | [PubMed]
 
Bremner JD, Randall P, Scott TM, et al: MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry  1995; 152:973—981
[PubMed]
 
Londborg PD, Hegel MT, Goldstein S: Sertraline treatment of posttraumatic stress disorder: results of 24 weeks of open-label continuation treatment. J Clin Psychiatry  2001; 62:325—331
[CrossRef] | [PubMed]
 
First MB, Spitzer RL, Gibbon M: Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). New York, New York State Psychiatric Institute, Biometrics Research, 1995
 
Main BF, Jones PJ, MacGillivray RT: Apolipoprotein E genotyping using the polymerase chain reaction and allele-specific oligonucleotide primers. J Lipid Res  1991; 32:183—187
[PubMed]
 
Wechsler D: Manual for the Wechsler Memory Scale-3rd ed. New York: Psychological Corporation, 1997
 
Heaton RK: Wisconsin Card Sorting Test Manual. Odessa, Fla, Psychological Assessment Resources, 1981
 
Peskind ER, Wilkinson CW, Petrie EC: Increased CSF cortisol in AD is a function of APOE genotype. Neurology  2001; 56(8):1094—1108
[PubMed]
 
Yehuda R: Current status of cortisol findings in post-traumatic stress disorder. Psychiatr Clin North Am  2002; 25:341—368
[CrossRef] | [PubMed]
 
Neylan TC, Schuff N, Lenoci M: Cortisol levels are positively correlated with hippocampal N-acetylaspartate. Biol Psychiatry  2003; 54:1118—1121
[CrossRef] | [PubMed]
 
+

References

Gallagher-Thompson D, O’Hara R, Simmons A: Apolipoprotein E epsilon4 allele affects the relationship between stress and depression in caregivers of patients with Alzheimer’s disease. J Geriatr Psychiatry Neurol  2001; 14:115—119
[CrossRef] | [PubMed]
 
Cohen RM, Small C, Lalonde F: Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women. Neurology  2001; 57:2223—2228
[PubMed]
 
Lippa CF, Smith TW, Saunders WB: Apolipoprotein E-epsilon 2 and Alzheimer’s disease: genotype influences pathologic phenotype. Neurology  1997; 48:515—519
[PubMed]
 
Flory JD, Manuck SB, Ferrell RE: Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. Am J Med Genet  2000; 96:707—711
[CrossRef] | [PubMed]
 
Kuller LH, Shemanski L, Manolio T: Relationship between APOE, MRI findings, and cognitive function in the Cardiovascular Health Study. Stroke  1998; 29:388—398
[CrossRef] | [PubMed]
 
Golier J, Yehuda R: Neuropsychological processes in post-traumatic stress disorder. Psychiatr Clin North Am  2002; 25:295—315
[CrossRef] | [PubMed]
 
Bremner JD, Randall P, Scott TM, et al: MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry  1995; 152:973—981
[PubMed]
 
Londborg PD, Hegel MT, Goldstein S: Sertraline treatment of posttraumatic stress disorder: results of 24 weeks of open-label continuation treatment. J Clin Psychiatry  2001; 62:325—331
[CrossRef] | [PubMed]
 
First MB, Spitzer RL, Gibbon M: Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). New York, New York State Psychiatric Institute, Biometrics Research, 1995
 
Main BF, Jones PJ, MacGillivray RT: Apolipoprotein E genotyping using the polymerase chain reaction and allele-specific oligonucleotide primers. J Lipid Res  1991; 32:183—187
[PubMed]
 
Wechsler D: Manual for the Wechsler Memory Scale-3rd ed. New York: Psychological Corporation, 1997
 
Heaton RK: Wisconsin Card Sorting Test Manual. Odessa, Fla, Psychological Assessment Resources, 1981
 
Peskind ER, Wilkinson CW, Petrie EC: Increased CSF cortisol in AD is a function of APOE genotype. Neurology  2001; 56(8):1094—1108
[PubMed]
 
Yehuda R: Current status of cortisol findings in post-traumatic stress disorder. Psychiatr Clin North Am  2002; 25:341—368
[CrossRef] | [PubMed]
 
Neylan TC, Schuff N, Lenoci M: Cortisol levels are positively correlated with hippocampal N-acetylaspartate. Biol Psychiatry  2003; 54:1118—1121
[CrossRef] | [PubMed]
 
+
+

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