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Apolipoprotein E ε4 allele frequency in elderly depressed patients with and without cerebrovascular disease
Journal of the Neurological Sciences 257 (2007) 280 – 283 www.elsevier.com/locate/jns
Apolipoprotein E ε4 allele frequency in elderly depressed patients with and without cerebrovascular disease Latchezar Traykov a,b,c,⁎, Anne Catherine Bayle a , Florence Latour a , Hermine Lenoir a , Marie-Laure Seux a , Olivier Hanon a , Renaud Péquignot a , Pierre Bert a , Florence Moulin a , Inge Cantegreil a , Emilie Wenisch a , Fériel Batouche a , Shima Mehrabian b , Jocelyne de Rotrou a , Anne-Sophie Rigaud a a Hôpital Broca, Paris, France Department of Neurology, Medical University, Sofia, Bulgaria c Hôpital Henri Mondor, University Paris XII, Créteil, France
b
Available online 6 March 2007
Abstract Late-onset depression (LOD) could be a very early manifestation of Alzheimer's disease (AD), although contradictory results have been reported. Cerebrovascular disease (CVD) may favor the development of LOD, and that the particular forms of vascular depression should be individualized. The Apolipoprotein E (ApoE) ε4 allele was shown to be a risk factor for AD. Its role in LOD is controversial, while it is still unknown in vascular depression. Our objective was to clarify the relationship between ApoE ε4 allele and LOD in patients with and without CVD. We examined the ApoE phenotypes in a sample of 311 subjects: 50 with vascular LOD, 24 with LOD without CVD, 115 with AD and 122 normal controls (NC). The study of the ApoE ε4 allele frequency showed significant differences between: AD group and the vascular LOD and NC groups; LOD group without CVD compared with NC group ( p b 0.05 to 0.001). The frequency of the ε4 allele in the LOD group without CVD did not differ significantly from the AD group, similarly the frequency of the ε4 allele in the vascular LOD group was not different from that in NC. The study suggests an association between the ApoE ε4 allele and the LOD without CVD. These patients could be at risk of developing AD by an ε4-dependent pathway. In contrast, the results show no association between the presence of ApoE ε4 allele and vascular depression and provide further evidence in support of the concept that ApoE ε4 allele is not associated with clinical CVD. © 2007 Elsevier B.V. All rights reserved. Keywords: Late-onset depression; Apolipoprotein E; Cerebrovascular disease; Vascular depression; Alzheimer's disease; Dementia
1. Introduction Depression has a poorer prognosis in the elderly than in young people. It could also be a very early manifestation of Alzheimer's disease (AD) [1,2], although some reports are contradictory in this respect [3,4].
⁎ Corresponding author. Medical University, University Hospital Alexandrovska, Department of Neurology, 1, St. Georgi Sofiiski str, 1431 Sofia, Bulgaria. Tel./fax: +359 2 952 67 87. E-mail address: [email protected] (L. Traykov). 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2007.01.038
Various researchers have looked for predictors of good and poor prognoses. Some authors have drawn a distinction between early-onset depression (EOD), i.e., the first episode of depressive illness occurring before the age of 60, and lateonset depression (LOD), the first episode occurring after the age of 60, and have raised the question of whether LOD is partly due to a biological aging process [5]. It has been suggested that cerebrovascular disease (CVD) may favour the development of late-onset depression, and that the particular forms of vascular depression should be individualized [6,7]. This suggestion was supported by studies reporting an association between clinically defined vascular
L. Traykov et al. / Journal of the Neurological Sciences 257 (2007) 280–283
risk factors and depression [6], as well as by the frequent occurrence of silent stroke and white matter changes detected by neuroimaging in LOD [7]. However, the role of the polymorphism of apolipoprotein E (ApoE) in the emergence of vascular depression is not quite well studied [8]. The ApoE ε4 allele (ApoE ε4) was shown to be a risk factor for AD [9], but the association of this allele with depression [10–12] or with CVD [13,14] remains controversial. The objective of our study was to clarify the relationship between ApoE ε4 allele and LOD in patients with and without CVD. We have recently reported preliminary data from a comparison of the ApoE phenotype of patients with vascular depression [15]. For the present study, we added more patients and analyzed the ApoE ε4 allele frequency of patients with late-onset depression without CVD and AD.
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evidence of relevant cerebrovascular disease by brain imaging were excluded from this group. 2.1.3. AD group One hundred fifteen patients (78 women and 37 men) were included in the AD group if they met the DSM-IV criteria for dementia of the Alzheimer type [19] and the NINCDSADRDA criteria for probable Alzheimer's disease [20]. 2.1.4. Normal controls group To compare the ApoE phenotypes and alleles distribution we composed control group of 122 elderly subjects (74 women and 48 men) with no history of vascular risk factors, no symptoms of psychiatric or neurological disease, no significant brain abnormalities on CT or MRI, and normal cognitive functions.
2. Materials and methods 2.2. ApoE phenotyping 2.1. Study population Patients were referred for diagnostic investigation of dementia to the Broca Hospital, Paris, France. The evaluation procedure consisted of a detailed recording of medical history, physical and neurological examinations, psychiatric and cognitive evaluations, and either brain computed tomography or magnetic resonance imaging. The psychiatric evaluation included a semistructured interview and the Geriatric Depression Scale (GDS) [16]. Cognitive status was evaluated by the Mini Mental State Examination (MMSE) [17] and a battery of neuropsychological screening tests [18]. All available information was evaluated by an experienced neurologist (who is also trained in brain imaging), psychiatrist, geriatrician and neuropsychologist. The clinical diagnoses were determined prior to ApoE analysis. Patients were included in the study after consensus have been reached for classification into one of the following diagnostic categories: 2.1.1. LOD with CVD group Fifty nondemented elderly patients (35 women and 15 men) met DSM-IV criteria [19] for a major depressive episode of the unipolar type (first onset of depression at 60 years of age or older). The vascular origin of depression was suggested by the presence of CT or MRI findings of infarcts or lacunae, and a history of at least 1 of 5 vascular factors: hypertension, heart disease, diabetes mellitus, hypercholesterolaemia, and peripheral vascular disease [6]. 2.1.2. LOD without CVD group Twenty four nondemented elderly patients (21 women and 3 men) were included in this group if they met the DSMIV criteria [19] for a major depressive episode of the unipolar type (first onset of depression at 60 years of age or older). None of these patients demonstrated focal neurological signs or radiological evidence of stroke. Patients with a history of vascular risk factors and/or cerebrovascular disease and/or
ApoE phenotyping was performed in all subjects by agarose isoelectric focusing immunoblot, blindly in relation to clinical diagnosis [21]. After subjects had been given a complete description of the study, written informed consent to participate was obtained. 2.3. Statistical analysis Inter-group differences in age and MMSE scores, were calculated by one-way analysis of variance (ANOVA). Significant main effects were submitted to post-hoc analysis by the Student–Newman–Keuls test (p b 0.05) for pair-wise differences between groups. Allele frequencies were estimated by assessing phenotype frequencies. Their distributions were analyzed using Pearson's χ2 test and Fisher's exact test, as appropriate. 3. Results The ANOVA showed no significant inter-group differences on age (Table 1). Post-hoc pair-wise comparison using Student–Newman–Keuls method ( p b 0.05) revealed that the scores for GDS were markedly higher in the depressed (with and without CVD) than in the AD and control groups, but were not significantly different between the joint.
Table 1 Population characteristics LOD without AD LOD with CVD (n = 50) CVD (n = 24) (n = 115) Age 76.3 (8.9) MMSE/30 28.1 (1.6) GDS/30 16.3 (4.3)
73.9 (7.7) 29.0 (1.2) 17.6 (4.1)
Controls (n = 122)
p
76.8 (6.9) 75.2 (6.3) 0.154 19.9 (4.7) 29.1 (1.1) b0.0001 6.8 (3.5) 6.3 (3.5) b0.0001
LOD = Late-Onset Depression; CVD = Cerebrovascular Disease; AD = Alzheimer's disease; MMSE = Mini Mental State Examination, GDS = Geriatric Depression Scale. Values are means (± SD).
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L. Traykov et al. / Journal of the Neurological Sciences 257 (2007) 280–283
Table 2 Apolipoprotein E phenotypes and alleles in patients and controls LOD with CVD (n = 50)
LOD without CVD (n = 24)
AD (n = 115)
Phenotypes E2/E2 n (%) E2/E3 n (%) E3/E3 n (%) E3/E4 n (%) E4/E4 n (%) E4/E2 n (%)
0 (0) 5 (10) 31 (62) 11 (22) 1 (2) 2 (4)
0 (0) 2 (8.3) 8 (33.4) 12 (50) 0 (0) 2 (8.3)
0 (0) 4 (3.5) 49 (42.6) 42 (36.5) 18 (15.7) 2 (1.7)
Alleles ε2 n (%) ε3 n (%) ε4 n (%)
7 (7) 78 (78) 15 (15)
4 (8.3) 30 (62.5) 14 (29.2)
6 (2.6) 144 (62.6) 80 (34.8)
Controls (n = 122) 0 15 77 27 0 3
(0) (12.3) (63.1) (22.1) (0) (2.5)
18 (7.4) 196 (80.3) 30 (12.3)
LOD = Late-Onset Depression; CVD = Cerebrovascular Disease; AD = Alzheimer's disease.
For MMSE, post-hoc pair-wise comparison showed that depressed patients (with and without CVD) and controls had significantly higher scores than AD patients. However, no significant difference was found between the depressed and control groups as regards the scores for MMSE. The ApoE phenotype and allele frequency distributions in the four groups are shown in Table 2. In the LOD with CVD group, ε4 allele frequency was not significantly different from control frequency (χ 2 = 0.35, p = .556), but was significantly lower than in AD (χ2 = 7.87, p = .005). However, in the LOD without CVD group, ε4 allele frequency was not significantly different from its frequency in AD (χ2 = 0.28, p = .594), but was significantly higher than in the controls (χ2 = 6.01, p = .014). Patients with at least one ε4 allele were more frequent among the AD (53.9%) and LOD without CVD (58.3%) groups than among the LOD with CVD (15.4%) and controls (24.6%). 4. Discussion The results of this study confirm that the ApoE ε4 allele occurs frequently in late-onset AD and we find similar association in late-onset depression without clinical cerebrovascular disease. In addition, the results show that the ApoE ε4 allele is not overrepresented in clinically defined lateonset vascular depression. Discrepant results have been reported concerning the link between ApoE ε4 and depression in elderly patients. Many investigators [22,23] found no association between depression as a whole in the elderly and the presence of ApoE ε4. However, when a distinction was drawn between EOD and LOD, some authors failed to find any difference in ApoE ε4 frequency [11], while others showed that ApoE ε4 was significantly overrepresented in LOD, but not in EOD [12]. These discrepant results might be owing to the heterogeneity of LOD, which probably comprises several subtypes with different vascular or neurodegenerative
aetiologies. Thus, we previously found an association between ApoE ε4 and LOD when the vascular subgroup was excluded [24]. It must be stressed, that while there is agreement about the association of the ApoE ε4 with AD, the relation between this allele and vascular dementia remains controversial. The results ranged from increased frequencies resembling those found for AD [13], to no association at all [14]. The divergent findings for ApoE ε4 frequency in vascular dementia might be owing to difficulties in reaching the clinical diagnosis of this dementia and to the differences between patient selection criteria. Patients with what is known as mixed vascular-degenerative dementia are often clinically indistinguishable from patients with AD or vascular dementia. In a previous study, we found that there was no association between ApoE ε4 and vascular dementia or cognitive impairment due to clinical CVD [25], but that ApoE ε4 was much more frequent in AD and mixed dementia. Such discrepancies highlight the advantage of classifying LOD, as far as possible, into neurodegenerative and vascular subgroups in order to study its physiopathology. The present findings, which show no association between ApoE ε4 and vascular depression, provide further evidence that the ApoE ε4 is not associated with CVD. There are some limitations to this study. First, the relatively small simple size, limits the interpretation of the data, although compared to other studies the present study has a comparable number of subjects. Second, a spurious increase in ApoE ε4 allele frequency in the subjects with LOD without CVD, may be due to a mistaken diagnosis (i.e. that they were suffering from AD with depression rather than primary major depression). Despite this, the detailed clinical and neuropsychological assessments, neuroimaging to clarify cerebral abnormalities and, finally, the use of a trained research team consisting of a geriatrician, neurologist, psychiatrist and neuropsychologist limited the chance for diagnostic misclassification. In conclusion, the study suggests an association between the ApoE ε4 allele and the LOD without CVD. This may indicate a predisposition for AD in this group. In contrast, the ApoE ε4 allele does not appear to be significantly associated with clinically diagnosed late-onset vascular depression. Subjects with late-onset depression without cerebrovascular disease may be in an early stage of some form of dementia that cannot be diagnosed at that stage, but manifests itself later. Alternatively, we cannot rule out the hypothesis that the ApoE ε4 allele is a risk factor for AD in elderly subjects with LOD. Future efforts should focus on long term longitudinal studies, to elucidate the course, the diagnostic outcome, and the neuropathology of LOD. References [1] Geerlings MI, Schoevers RA, Beekman AT, Jonker C, Deeg DJ, Schmand B, et al. Depression and risk of cognitive decline and Alzheimer's disease. Results of two prospective community-based studies in The Netherlands. Br J Psychiatry 2000;176:568–75.
L. Traykov et al. / Journal of the Neurological Sciences 257 (2007) 280–283 [2] Green RC, Cupples LA, Kurz A, Auerbach S, Sadovnick R, Go D, et al. Depression as a risk factor for Alzheimer disease: the MIRAGE study. Arch Neurol 2003;60:753–9. [3] Henderson AS, Korten AE, Jacomb PA, Mackinnon AJ, Jorm AF, Christensen H, et al. The course of depression in the elderly: a longitudinal community-based study in Australia. Psychol Med 1997;27:119–29. [4] Vinkers DJ, Gussekloo J, Stek ML, Westendorp RGJ, van der Mast RC. Temporal relation between depression and cognitive impairment in old age: prospective population based study. BMJ 2004;329:881–3. [5] Burvill PW, Hall WD, Stampfer KG, Emmerson JP. A comparison of early-onset and late-onset depressive illness in the elderly. Br J Psychiatr 1989;155:673–9. [6] Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Silbersweig D, Charlson M. Clinically defined vascular depression. Am J Psychiatry 1997;154:562–5. [7] Krishnan KRR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry 1997;154:497–501. [8] Cervilla J, Prince M, Joels S, Russ C, Lovestone S. Genes related to vascular disease (APOE, VLDL-R, DCP-1) and other vascular factors in late-life depression. Am J Geriatr Psychiatry 2004;12:202–10. [9] Roses A, Strittmatter W, Saunders A, Schmechel D, Pericak-Vance M. Apolipoprotein E and Alzheimer's disease: state of the field after two years. In: Roses A, Weisgraber K, Christen Y, editors. Apolipoprotein E and Alzheimer's Disease. Berlin: Springer; 1996. p. 1–10. [10] Zubenko GS, Henderson R, Stiffler JS, Stabler S, Rosen J, Kaplan BB. Association of the APOE ε4 allele with clinical subtypes of late life depression. Biol Psychiatry 1996;40:1008–16. [11] Schmand B, Hooijer C, Jonker C, Lindeboom J, Havekes LM. Apolipoprotein E phenotype is not related to late-life depression in a populationbased sample. Soc Psychiatry Psychiatr Epidemiol 1998;33:21–6. [12] Krishnan KRR, Tupler LA, Ritchie JC, McDonald WM, Knight DL, Nemeroff CB, et al. Apolipoprotein E-ε4 frequency in geriatric depression. Biol Psychiatry 1996;40:69–71. [13] Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam study. Lancet 1997;349:151–4. [14] Dickson DW, Roy N, Graff-Radford D, Perez-Tur J, Hardy J, Pearl G, et al. Apolipoprotein-E genotype influences amyloid deposition and limbic neurofibrillary degeneration, but not lewy body or vascular pathologies in postmortem brains. Neurology 1999;52(Suppl 2):562–3.
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[15] Rigaud AS, Latour F, Moulin F, Forette F, Traykov L, Boller F. Apolipoprotein E epsilon4 allele and clinically defined vascular depression. Arch Gen Psychiatry 2002;59:290–1. [16] Yesavage J, Brink TL. Development and validation of a Geriatric Depression Screening Scale: a preliminary report. J Psychiatr Res 1983;17:37–49. [17] Folstein MF, Folstein SE, Mc Hugh PR. “Mini-mental test”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. [18] De Rotrou J, Forette F, Hervy MP, Tortrat D, Fermanian J, Boudou MR, et al. The cognitive efficiency profile: description and validation in patients with Alzheimer disease. Int J Geriatr Psychiatry 1991;6:501–19. [19] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. [20] Mckhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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 disease. Neurology 1984;34:939–44. [21] Bailleul S, Couderc R, Landais V, Lefevre G, Raichvarg D, Etienne J. Direct phenotyping of human apolipoprotein E in plasma: application to population frequency distribution in Paris (France). Hum Hered 1993;43:159–65. [22] Steffens DC, Norton MC, Hart AD, Skoog I, Corcoran C, Breitner JC, Cache County Study Group. Apolipoprotein E genotype and major depression in a community of older adults. The Cache County study. Psychol Med 2003;33:541–7. [23] Mauricio M, O'Hara R, Yesavage JA, Friedman L, Kraemer HC, Van De Water M, et al. A longitudinal study of apolipoprotein-E genotype and depressive symptoms in community-dwelling older adults. Am J Geriatr Psychiatry 2000;8:196–200. [24] Rigaud AS, Traykov L, Caputo L, Coste J, Latour F, Couderc R, et al. Association of the apolipoprotein E epsilon4 allele with late-onset depression. Neuroepidemiology 2001;20:268–72. [25] Traykov L, Rigaud AS, Baudic S, Smagghe A, Boller F, Forette F. Apolipoprotein E varepsilon ε4 allele frequency in demented and cognitively impaired patients with and without cerebrovascular disease. J Neurol Sci 2002(203–204):177–81.
Apolipoprotein E ε4 allele frequency in elderly depressed patients with and without cerebrovascular disease Latchezar Traykov a,b,c,⁎, Anne Catherine Bayle a , Florence Latour a , Hermine Lenoir a , Marie-Laure Seux a , Olivier Hanon a , Renaud Péquignot a , Pierre Bert a , Florence Moulin a , Inge Cantegreil a , Emilie Wenisch a , Fériel Batouche a , Shima Mehrabian b , Jocelyne de Rotrou a , Anne-Sophie Rigaud a a Hôpital Broca, Paris, France Department of Neurology, Medical University, Sofia, Bulgaria c Hôpital Henri Mondor, University Paris XII, Créteil, France
b
Available online 6 March 2007
Abstract Late-onset depression (LOD) could be a very early manifestation of Alzheimer's disease (AD), although contradictory results have been reported. Cerebrovascular disease (CVD) may favor the development of LOD, and that the particular forms of vascular depression should be individualized. The Apolipoprotein E (ApoE) ε4 allele was shown to be a risk factor for AD. Its role in LOD is controversial, while it is still unknown in vascular depression. Our objective was to clarify the relationship between ApoE ε4 allele and LOD in patients with and without CVD. We examined the ApoE phenotypes in a sample of 311 subjects: 50 with vascular LOD, 24 with LOD without CVD, 115 with AD and 122 normal controls (NC). The study of the ApoE ε4 allele frequency showed significant differences between: AD group and the vascular LOD and NC groups; LOD group without CVD compared with NC group ( p b 0.05 to 0.001). The frequency of the ε4 allele in the LOD group without CVD did not differ significantly from the AD group, similarly the frequency of the ε4 allele in the vascular LOD group was not different from that in NC. The study suggests an association between the ApoE ε4 allele and the LOD without CVD. These patients could be at risk of developing AD by an ε4-dependent pathway. In contrast, the results show no association between the presence of ApoE ε4 allele and vascular depression and provide further evidence in support of the concept that ApoE ε4 allele is not associated with clinical CVD. © 2007 Elsevier B.V. All rights reserved. Keywords: Late-onset depression; Apolipoprotein E; Cerebrovascular disease; Vascular depression; Alzheimer's disease; Dementia
1. Introduction Depression has a poorer prognosis in the elderly than in young people. It could also be a very early manifestation of Alzheimer's disease (AD) [1,2], although some reports are contradictory in this respect [3,4].
⁎ Corresponding author. Medical University, University Hospital Alexandrovska, Department of Neurology, 1, St. Georgi Sofiiski str, 1431 Sofia, Bulgaria. Tel./fax: +359 2 952 67 87. E-mail address: [email protected] (L. Traykov). 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2007.01.038
Various researchers have looked for predictors of good and poor prognoses. Some authors have drawn a distinction between early-onset depression (EOD), i.e., the first episode of depressive illness occurring before the age of 60, and lateonset depression (LOD), the first episode occurring after the age of 60, and have raised the question of whether LOD is partly due to a biological aging process [5]. It has been suggested that cerebrovascular disease (CVD) may favour the development of late-onset depression, and that the particular forms of vascular depression should be individualized [6,7]. This suggestion was supported by studies reporting an association between clinically defined vascular
L. Traykov et al. / Journal of the Neurological Sciences 257 (2007) 280–283
risk factors and depression [6], as well as by the frequent occurrence of silent stroke and white matter changes detected by neuroimaging in LOD [7]. However, the role of the polymorphism of apolipoprotein E (ApoE) in the emergence of vascular depression is not quite well studied [8]. The ApoE ε4 allele (ApoE ε4) was shown to be a risk factor for AD [9], but the association of this allele with depression [10–12] or with CVD [13,14] remains controversial. The objective of our study was to clarify the relationship between ApoE ε4 allele and LOD in patients with and without CVD. We have recently reported preliminary data from a comparison of the ApoE phenotype of patients with vascular depression [15]. For the present study, we added more patients and analyzed the ApoE ε4 allele frequency of patients with late-onset depression without CVD and AD.
281
evidence of relevant cerebrovascular disease by brain imaging were excluded from this group. 2.1.3. AD group One hundred fifteen patients (78 women and 37 men) were included in the AD group if they met the DSM-IV criteria for dementia of the Alzheimer type [19] and the NINCDSADRDA criteria for probable Alzheimer's disease [20]. 2.1.4. Normal controls group To compare the ApoE phenotypes and alleles distribution we composed control group of 122 elderly subjects (74 women and 48 men) with no history of vascular risk factors, no symptoms of psychiatric or neurological disease, no significant brain abnormalities on CT or MRI, and normal cognitive functions.
2. Materials and methods 2.2. ApoE phenotyping 2.1. Study population Patients were referred for diagnostic investigation of dementia to the Broca Hospital, Paris, France. The evaluation procedure consisted of a detailed recording of medical history, physical and neurological examinations, psychiatric and cognitive evaluations, and either brain computed tomography or magnetic resonance imaging. The psychiatric evaluation included a semistructured interview and the Geriatric Depression Scale (GDS) [16]. Cognitive status was evaluated by the Mini Mental State Examination (MMSE) [17] and a battery of neuropsychological screening tests [18]. All available information was evaluated by an experienced neurologist (who is also trained in brain imaging), psychiatrist, geriatrician and neuropsychologist. The clinical diagnoses were determined prior to ApoE analysis. Patients were included in the study after consensus have been reached for classification into one of the following diagnostic categories: 2.1.1. LOD with CVD group Fifty nondemented elderly patients (35 women and 15 men) met DSM-IV criteria [19] for a major depressive episode of the unipolar type (first onset of depression at 60 years of age or older). The vascular origin of depression was suggested by the presence of CT or MRI findings of infarcts or lacunae, and a history of at least 1 of 5 vascular factors: hypertension, heart disease, diabetes mellitus, hypercholesterolaemia, and peripheral vascular disease [6]. 2.1.2. LOD without CVD group Twenty four nondemented elderly patients (21 women and 3 men) were included in this group if they met the DSMIV criteria [19] for a major depressive episode of the unipolar type (first onset of depression at 60 years of age or older). None of these patients demonstrated focal neurological signs or radiological evidence of stroke. Patients with a history of vascular risk factors and/or cerebrovascular disease and/or
ApoE phenotyping was performed in all subjects by agarose isoelectric focusing immunoblot, blindly in relation to clinical diagnosis [21]. After subjects had been given a complete description of the study, written informed consent to participate was obtained. 2.3. Statistical analysis Inter-group differences in age and MMSE scores, were calculated by one-way analysis of variance (ANOVA). Significant main effects were submitted to post-hoc analysis by the Student–Newman–Keuls test (p b 0.05) for pair-wise differences between groups. Allele frequencies were estimated by assessing phenotype frequencies. Their distributions were analyzed using Pearson's χ2 test and Fisher's exact test, as appropriate. 3. Results The ANOVA showed no significant inter-group differences on age (Table 1). Post-hoc pair-wise comparison using Student–Newman–Keuls method ( p b 0.05) revealed that the scores for GDS were markedly higher in the depressed (with and without CVD) than in the AD and control groups, but were not significantly different between the joint.
Table 1 Population characteristics LOD without AD LOD with CVD (n = 50) CVD (n = 24) (n = 115) Age 76.3 (8.9) MMSE/30 28.1 (1.6) GDS/30 16.3 (4.3)
73.9 (7.7) 29.0 (1.2) 17.6 (4.1)
Controls (n = 122)
p
76.8 (6.9) 75.2 (6.3) 0.154 19.9 (4.7) 29.1 (1.1) b0.0001 6.8 (3.5) 6.3 (3.5) b0.0001
LOD = Late-Onset Depression; CVD = Cerebrovascular Disease; AD = Alzheimer's disease; MMSE = Mini Mental State Examination, GDS = Geriatric Depression Scale. Values are means (± SD).
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L. Traykov et al. / Journal of the Neurological Sciences 257 (2007) 280–283
Table 2 Apolipoprotein E phenotypes and alleles in patients and controls LOD with CVD (n = 50)
LOD without CVD (n = 24)
AD (n = 115)
Phenotypes E2/E2 n (%) E2/E3 n (%) E3/E3 n (%) E3/E4 n (%) E4/E4 n (%) E4/E2 n (%)
0 (0) 5 (10) 31 (62) 11 (22) 1 (2) 2 (4)
0 (0) 2 (8.3) 8 (33.4) 12 (50) 0 (0) 2 (8.3)
0 (0) 4 (3.5) 49 (42.6) 42 (36.5) 18 (15.7) 2 (1.7)
Alleles ε2 n (%) ε3 n (%) ε4 n (%)
7 (7) 78 (78) 15 (15)
4 (8.3) 30 (62.5) 14 (29.2)
6 (2.6) 144 (62.6) 80 (34.8)
Controls (n = 122) 0 15 77 27 0 3
(0) (12.3) (63.1) (22.1) (0) (2.5)
18 (7.4) 196 (80.3) 30 (12.3)
LOD = Late-Onset Depression; CVD = Cerebrovascular Disease; AD = Alzheimer's disease.
For MMSE, post-hoc pair-wise comparison showed that depressed patients (with and without CVD) and controls had significantly higher scores than AD patients. However, no significant difference was found between the depressed and control groups as regards the scores for MMSE. The ApoE phenotype and allele frequency distributions in the four groups are shown in Table 2. In the LOD with CVD group, ε4 allele frequency was not significantly different from control frequency (χ 2 = 0.35, p = .556), but was significantly lower than in AD (χ2 = 7.87, p = .005). However, in the LOD without CVD group, ε4 allele frequency was not significantly different from its frequency in AD (χ2 = 0.28, p = .594), but was significantly higher than in the controls (χ2 = 6.01, p = .014). Patients with at least one ε4 allele were more frequent among the AD (53.9%) and LOD without CVD (58.3%) groups than among the LOD with CVD (15.4%) and controls (24.6%). 4. Discussion The results of this study confirm that the ApoE ε4 allele occurs frequently in late-onset AD and we find similar association in late-onset depression without clinical cerebrovascular disease. In addition, the results show that the ApoE ε4 allele is not overrepresented in clinically defined lateonset vascular depression. Discrepant results have been reported concerning the link between ApoE ε4 and depression in elderly patients. Many investigators [22,23] found no association between depression as a whole in the elderly and the presence of ApoE ε4. However, when a distinction was drawn between EOD and LOD, some authors failed to find any difference in ApoE ε4 frequency [11], while others showed that ApoE ε4 was significantly overrepresented in LOD, but not in EOD [12]. These discrepant results might be owing to the heterogeneity of LOD, which probably comprises several subtypes with different vascular or neurodegenerative
aetiologies. Thus, we previously found an association between ApoE ε4 and LOD when the vascular subgroup was excluded [24]. It must be stressed, that while there is agreement about the association of the ApoE ε4 with AD, the relation between this allele and vascular dementia remains controversial. The results ranged from increased frequencies resembling those found for AD [13], to no association at all [14]. The divergent findings for ApoE ε4 frequency in vascular dementia might be owing to difficulties in reaching the clinical diagnosis of this dementia and to the differences between patient selection criteria. Patients with what is known as mixed vascular-degenerative dementia are often clinically indistinguishable from patients with AD or vascular dementia. In a previous study, we found that there was no association between ApoE ε4 and vascular dementia or cognitive impairment due to clinical CVD [25], but that ApoE ε4 was much more frequent in AD and mixed dementia. Such discrepancies highlight the advantage of classifying LOD, as far as possible, into neurodegenerative and vascular subgroups in order to study its physiopathology. The present findings, which show no association between ApoE ε4 and vascular depression, provide further evidence that the ApoE ε4 is not associated with CVD. There are some limitations to this study. First, the relatively small simple size, limits the interpretation of the data, although compared to other studies the present study has a comparable number of subjects. Second, a spurious increase in ApoE ε4 allele frequency in the subjects with LOD without CVD, may be due to a mistaken diagnosis (i.e. that they were suffering from AD with depression rather than primary major depression). Despite this, the detailed clinical and neuropsychological assessments, neuroimaging to clarify cerebral abnormalities and, finally, the use of a trained research team consisting of a geriatrician, neurologist, psychiatrist and neuropsychologist limited the chance for diagnostic misclassification. In conclusion, the study suggests an association between the ApoE ε4 allele and the LOD without CVD. This may indicate a predisposition for AD in this group. In contrast, the ApoE ε4 allele does not appear to be significantly associated with clinically diagnosed late-onset vascular depression. Subjects with late-onset depression without cerebrovascular disease may be in an early stage of some form of dementia that cannot be diagnosed at that stage, but manifests itself later. Alternatively, we cannot rule out the hypothesis that the ApoE ε4 allele is a risk factor for AD in elderly subjects with LOD. Future efforts should focus on long term longitudinal studies, to elucidate the course, the diagnostic outcome, and the neuropathology of LOD. References [1] Geerlings MI, Schoevers RA, Beekman AT, Jonker C, Deeg DJ, Schmand B, et al. Depression and risk of cognitive decline and Alzheimer's disease. Results of two prospective community-based studies in The Netherlands. Br J Psychiatry 2000;176:568–75.
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