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APOE genotype in cerebrovascular disease and vascular dementia
Journal of the Neurological Sciences 203 – 204 (2002) 173 – 176 www.elsevier.com/locate/jns
APOE genotype in cerebrovascular disease and vascular dementia A. Frank a,*, E. Dı´ez-Tejedor a, M.J. Bullido b, F. Valdivieso b, P. Barreiro a a
Department of Neurology, Hospital Universitario La Paz, Universidad Auto´noma de Madrid, Paseo de la Castellana, 261-28046 Madrid, Spain b Department of Molecular Genetics Severo Ochoa, Universidad Auto´noma de Madrid, Madrid, Spain
Abstract Background: The fact that the allele q4 of the Apolipoprotein E (APOE) gene could act like a risk factor not only in late-onset familial and sporadic Alzheimer’s disease (AD) but also in cerebrovascular disease (CVD) and vascular dementia (VaD) is still controversial. Methods: In order to study if q4 allele is overrepresented not only in AD but also in CVD and VaD, APOE genotyping was undertaken in a series of 247 patients: 26 cases with VaD, 41 cases with CVD but without cognitive impairment (CVD-C), 83 cases with AD and 97 aged-matched ‘‘healthy controls’’ (HC). Results: Percentages of subjects bearing one or two copies of the q4 allele was much higher in AD patients (54%) than in either CVD-C (29%) ( p < 0.05), VaD (15%) ( p < 0.001) or HC (13%) ( p < 0.001). Conclusions: These results strengthen the hypothesis that involves the APOE q4 allele as a predisposing factor for AD, but not for CVD or VaD. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Vascular dementia; Cerebrovascular disease; ApoE
1. Introduction Apolipoprotein E (ApoE) is the most important cholesterol-transporting protein and one of the major components of very low density lipoproteins (VLDL). It is supposed that it also plays a certain role in the central nervous system homeostasis, which is yet not well known [1,2]. The APOE gene is located on chromosome 19 and it has three main allelic isoforms (q2, q3, q4), with q3 being the most frequent among general population. It has been suggested that allele q3 could act like a protection factor favoring neuronal cytoskeleton regeneration [3,4]. By contrast, its absence might increase susceptibility to abnormal TAU protein hyperphosphorylation and neurofibrillary tangles formation. Allele q4 could represent a biologically active factor for deposition of h-amyloid peptide in the brain, and so might contribute in AD pathogenesis. Moreover, it also could make the brain more vulnerable against several aggressions, such as cranial traumatisms or cerebrovascular insults, leading in some instances to an irreversible neuronal damage [5– 7]. Since 1993, it is known that the q4 allele of the gene APOE is a predisposing factor for late-onset, sporadic and familial Alzheimer’s disease (AD) [8]. Several groups have reported a possible influence of APOE genotype not only in AD, but also in other conditions * Corresponding author. E-mail address: [email protected] (A. Frank).
such as age-related memory decline [9], preclinical stage of possible AD [10], Parkinson’s disease [11], Down’s syndrome [12] or cerebrovascular disease (CVD) and VaD [13]. The fact that the allele q4 of APOE could act like a risk factor not only in late-onset familial and sporadic AD but also in cerebrovascular disease (CVD) and vascular dementia (VaD) is still controversial [6,7,14 – 18] and remains a matter of study. Our aim was to examine the association between APOE status (frequency of alleles q3 and q4) and some conditions, either with dementia (AD and VaD) or without dementia (cerebrovascular disease without dementia, considered as cerebrovascular disease controls (CVD-C) and healthy controls (HC)). We also wanted to study if allelle q4 is overrepresented not only in AD, but also in VaD and CVD-C patients as compared with HC.
2. Patients and methods A series of 247 subjects was studied in the Department of Neurology between the years 1995 and 1997. Each subject was informed of the aim of the study, and all gave their consent to participate. A clinical history, a neurological examination as well as a neuropsychological evaluation and a mini-mental state examination were performed in all the subjects. The classi-
0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 5 1 0 X ( 0 2 ) 0 0 2 8 6 - 1
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A. Frank et al. / Journal of the Neurological Sciences 203 – 204 (2002) 173–176
fication of the sample was done on clinical criteria as healthy controls, vascular controls or patients with dementia. In the latter group, Alzheimer’s disease was diagnosed in patients who fulfilled NINCDS-ADRDA criteria for AD, and vascular dementia was diagnosed in patients who fulfilled ICD-10 criteria for VaD. A neuroradiological study (CT or MRI) was done not only in CVD patients but also in control healthy subjects or in AD patients. For the genetic study, blood sample (10 cm3) was collected from an antecubital vein, and APOE genotyping was undertaken by the restriction fragment length polymorphism (RFLP) technique. Data were statistically analyzed (Student’s t-test, v2 test, ANOVA).
3. Results Out of the whole sample, 67 patients had CVD: 26 of them met ICD-10 criteria for VaD, whereas 41 subjects did not show any cognitive impairment, so they were considered as ‘‘CVD controls’’ (CVD-C). Subjects without evidence of CVD comprised 83 cases who fulfilled NINCDSADRDA criteria for AD and 97 aged-matched people (in most instances, they were the patients’ spouses) who were considered as ‘‘healthy controls’’ (HC). Table 1 shows demographic data as well as cognitive measures (MEC, Blessed’s scale, CDR and Rosen’s scale for ischemia). Table 2 shows percentages of subjects bearing one or two copies of the q4 allele. The presence of allele APOE-4 is statistically more frequent in AD patients (44 out of 83 = 54%) than in HC (13 out of 97 = 13%) ( p < 0.001) but not in VaD patients (4 out of 26 = 15%). In the group of patients with cerebrovascular disease (CVD), q4 allele frequency did not show statistical difference between CVD-C and VaD.
Table 1 Clinical data AD Number of subjects Gender (M = male/ F = female) Age (years) (mean F S.D.) Mental state examination (mean F S.D.) Blessed’s scale (mean F S.D.)
VaD
CVD-C
HC
41 15 F/26 M
97 63 F/34 M
69.3 F 6.7
73.4 F 6.6* 67.1 F 6.6
67.1 F 7.6
16 F 8
20 F 5.1
33 F 2.8**
30.5 F 3.2**
12.5 F 6.7
12.2 F 5.5
2.2 F 1.9** 0.75 F 1.0*
83 26 53 F/30 M 6 F/20 M
AD = Alzheimer’s disease; VaD = vascular dementia; CVD-C = cerebrovascular disease controls; HC = healthy controls. * p < 0.05 compared with AD. ** p < 0.001 compared with AD.
Table 2 Percentages of APOE alleles VD (N = 26) APOE 4 +
APOE 4
CVDC (N = 38)
HC (N = 97)
AD (N = 83)
4 (15%)
11 (29%) 13 (13%) 44 (54%) p < 0.05 vs. HC p < 0.001 vs. HC and p < 0.05 vs. CVD-C 22 (85%) 27 (71%) 84 (87%) 38 (46%)
AD = Alzheimer’s disease; VaD = vascular dementia; CVD-C = cerebrovascular disease controls; HC = healthy controls.
When comparing the q4 allele frequency in nondemented subjects, a statistical difference was found between CVD-C subjects (11 out of 38 = 29%) and HC ( p < 0.05); however, because of the small sample size, it is not clear enough whether this difference is sufficiently consistent to be taken into account. Our study shows that q4 allele frequency is clearly much higher in AD than in HC but not in patients with CVD (either VaD or CVD-C) as compared to HC.
4. Discussion Some reports suggest a relationship between APOE-4 allele and high mortality after cerebral haemorrhage [19] or cognitive decline after cardiac by-pass surgery [20] or cardiovascular disease [21]. Some studies suggest that APOE q4 may play a role in dementia with stroke and vascular dementia (VaD) [7], and a possible association between APOE q4 allele and ischemic stroke with or without AD has also been reported in some other studies [22 – 28]. These hypotheses are attractive because it is known that risk either for stroke or VaD is attributable to the vagaries of lipoprotein metabolism. Some researchers think that APOE-4 could induce atherosclerosis by its influence in increasing plasmatic low-density lipoprotein (LDL) cholesterol fraction levels [29]. However, these associations have not been supported in other studies [16,30 – 36]. Others think that the presence of allele APOE-4 seems to increase the risk of dementia and AD independently of its effect on dyslipidemia and atherogenesis [37]. Others point out the possible relationship with other polymorphisms different from APOE [38]. Besides, many studies are based only on clinical and not pathological criteria. This fact may result in imperfect classification of VaD. Other studies have focused its attention on the possible influence of APOE genotype on white matter hyperintensities seen on magnetic resonance imaging (MRI) in AD and the most of them report no association between allele q4 and white matter changes [30,39 –42]. At the same time, other possible interaction between classical vascular risk factors like arterial hypertension, ischemic cardiopathy, hyperlipemia, stroke, etc. and AD on one side and predisposing factors for AD, like APOE status, female gender, mother’s age at birth, etc. and VaD on
A. Frank et al. / Journal of the Neurological Sciences 203 – 204 (2002) 173–176
the other side, are matters of research. For example, it has been reported that high concentrations of low-density cholesterol lipoprotein are associated with a high risk of dementia with stroke [43]. In our results, the higher percentage of subjects bearing the q4 allele in the AD group compared to the HC group is similar to previous reports and the existing literature of the subject in agreement. Regarding literature controversy about APOE and CVD, our results show no association between CVD or VaD and APOE-4. We conclude that these results support the hypothesis that the APOE q4 allele is a predisposing factor for AD, but not for CVD or VaD. To confirm whether bearing one or two copies of the q4 allele increases susceptibility to cerebrovascular diseases requires a larger prospective study.
[15]
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[19]
[20]
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APOE genotype in cerebrovascular disease and vascular dementia A. Frank a,*, E. Dı´ez-Tejedor a, M.J. Bullido b, F. Valdivieso b, P. Barreiro a a
Department of Neurology, Hospital Universitario La Paz, Universidad Auto´noma de Madrid, Paseo de la Castellana, 261-28046 Madrid, Spain b Department of Molecular Genetics Severo Ochoa, Universidad Auto´noma de Madrid, Madrid, Spain
Abstract Background: The fact that the allele q4 of the Apolipoprotein E (APOE) gene could act like a risk factor not only in late-onset familial and sporadic Alzheimer’s disease (AD) but also in cerebrovascular disease (CVD) and vascular dementia (VaD) is still controversial. Methods: In order to study if q4 allele is overrepresented not only in AD but also in CVD and VaD, APOE genotyping was undertaken in a series of 247 patients: 26 cases with VaD, 41 cases with CVD but without cognitive impairment (CVD-C), 83 cases with AD and 97 aged-matched ‘‘healthy controls’’ (HC). Results: Percentages of subjects bearing one or two copies of the q4 allele was much higher in AD patients (54%) than in either CVD-C (29%) ( p < 0.05), VaD (15%) ( p < 0.001) or HC (13%) ( p < 0.001). Conclusions: These results strengthen the hypothesis that involves the APOE q4 allele as a predisposing factor for AD, but not for CVD or VaD. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Vascular dementia; Cerebrovascular disease; ApoE
1. Introduction Apolipoprotein E (ApoE) is the most important cholesterol-transporting protein and one of the major components of very low density lipoproteins (VLDL). It is supposed that it also plays a certain role in the central nervous system homeostasis, which is yet not well known [1,2]. The APOE gene is located on chromosome 19 and it has three main allelic isoforms (q2, q3, q4), with q3 being the most frequent among general population. It has been suggested that allele q3 could act like a protection factor favoring neuronal cytoskeleton regeneration [3,4]. By contrast, its absence might increase susceptibility to abnormal TAU protein hyperphosphorylation and neurofibrillary tangles formation. Allele q4 could represent a biologically active factor for deposition of h-amyloid peptide in the brain, and so might contribute in AD pathogenesis. Moreover, it also could make the brain more vulnerable against several aggressions, such as cranial traumatisms or cerebrovascular insults, leading in some instances to an irreversible neuronal damage [5– 7]. Since 1993, it is known that the q4 allele of the gene APOE is a predisposing factor for late-onset, sporadic and familial Alzheimer’s disease (AD) [8]. Several groups have reported a possible influence of APOE genotype not only in AD, but also in other conditions * Corresponding author. E-mail address: [email protected] (A. Frank).
such as age-related memory decline [9], preclinical stage of possible AD [10], Parkinson’s disease [11], Down’s syndrome [12] or cerebrovascular disease (CVD) and VaD [13]. The fact that the allele q4 of APOE could act like a risk factor not only in late-onset familial and sporadic AD but also in cerebrovascular disease (CVD) and vascular dementia (VaD) is still controversial [6,7,14 – 18] and remains a matter of study. Our aim was to examine the association between APOE status (frequency of alleles q3 and q4) and some conditions, either with dementia (AD and VaD) or without dementia (cerebrovascular disease without dementia, considered as cerebrovascular disease controls (CVD-C) and healthy controls (HC)). We also wanted to study if allelle q4 is overrepresented not only in AD, but also in VaD and CVD-C patients as compared with HC.
2. Patients and methods A series of 247 subjects was studied in the Department of Neurology between the years 1995 and 1997. Each subject was informed of the aim of the study, and all gave their consent to participate. A clinical history, a neurological examination as well as a neuropsychological evaluation and a mini-mental state examination were performed in all the subjects. The classi-
0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 5 1 0 X ( 0 2 ) 0 0 2 8 6 - 1
174
A. Frank et al. / Journal of the Neurological Sciences 203 – 204 (2002) 173–176
fication of the sample was done on clinical criteria as healthy controls, vascular controls or patients with dementia. In the latter group, Alzheimer’s disease was diagnosed in patients who fulfilled NINCDS-ADRDA criteria for AD, and vascular dementia was diagnosed in patients who fulfilled ICD-10 criteria for VaD. A neuroradiological study (CT or MRI) was done not only in CVD patients but also in control healthy subjects or in AD patients. For the genetic study, blood sample (10 cm3) was collected from an antecubital vein, and APOE genotyping was undertaken by the restriction fragment length polymorphism (RFLP) technique. Data were statistically analyzed (Student’s t-test, v2 test, ANOVA).
3. Results Out of the whole sample, 67 patients had CVD: 26 of them met ICD-10 criteria for VaD, whereas 41 subjects did not show any cognitive impairment, so they were considered as ‘‘CVD controls’’ (CVD-C). Subjects without evidence of CVD comprised 83 cases who fulfilled NINCDSADRDA criteria for AD and 97 aged-matched people (in most instances, they were the patients’ spouses) who were considered as ‘‘healthy controls’’ (HC). Table 1 shows demographic data as well as cognitive measures (MEC, Blessed’s scale, CDR and Rosen’s scale for ischemia). Table 2 shows percentages of subjects bearing one or two copies of the q4 allele. The presence of allele APOE-4 is statistically more frequent in AD patients (44 out of 83 = 54%) than in HC (13 out of 97 = 13%) ( p < 0.001) but not in VaD patients (4 out of 26 = 15%). In the group of patients with cerebrovascular disease (CVD), q4 allele frequency did not show statistical difference between CVD-C and VaD.
Table 1 Clinical data AD Number of subjects Gender (M = male/ F = female) Age (years) (mean F S.D.) Mental state examination (mean F S.D.) Blessed’s scale (mean F S.D.)
VaD
CVD-C
HC
41 15 F/26 M
97 63 F/34 M
69.3 F 6.7
73.4 F 6.6* 67.1 F 6.6
67.1 F 7.6
16 F 8
20 F 5.1
33 F 2.8**
30.5 F 3.2**
12.5 F 6.7
12.2 F 5.5
2.2 F 1.9** 0.75 F 1.0*
83 26 53 F/30 M 6 F/20 M
AD = Alzheimer’s disease; VaD = vascular dementia; CVD-C = cerebrovascular disease controls; HC = healthy controls. * p < 0.05 compared with AD. ** p < 0.001 compared with AD.
Table 2 Percentages of APOE alleles VD (N = 26) APOE 4 +
APOE 4
CVDC (N = 38)
HC (N = 97)
AD (N = 83)
4 (15%)
11 (29%) 13 (13%) 44 (54%) p < 0.05 vs. HC p < 0.001 vs. HC and p < 0.05 vs. CVD-C 22 (85%) 27 (71%) 84 (87%) 38 (46%)
AD = Alzheimer’s disease; VaD = vascular dementia; CVD-C = cerebrovascular disease controls; HC = healthy controls.
When comparing the q4 allele frequency in nondemented subjects, a statistical difference was found between CVD-C subjects (11 out of 38 = 29%) and HC ( p < 0.05); however, because of the small sample size, it is not clear enough whether this difference is sufficiently consistent to be taken into account. Our study shows that q4 allele frequency is clearly much higher in AD than in HC but not in patients with CVD (either VaD or CVD-C) as compared to HC.
4. Discussion Some reports suggest a relationship between APOE-4 allele and high mortality after cerebral haemorrhage [19] or cognitive decline after cardiac by-pass surgery [20] or cardiovascular disease [21]. Some studies suggest that APOE q4 may play a role in dementia with stroke and vascular dementia (VaD) [7], and a possible association between APOE q4 allele and ischemic stroke with or without AD has also been reported in some other studies [22 – 28]. These hypotheses are attractive because it is known that risk either for stroke or VaD is attributable to the vagaries of lipoprotein metabolism. Some researchers think that APOE-4 could induce atherosclerosis by its influence in increasing plasmatic low-density lipoprotein (LDL) cholesterol fraction levels [29]. However, these associations have not been supported in other studies [16,30 – 36]. Others think that the presence of allele APOE-4 seems to increase the risk of dementia and AD independently of its effect on dyslipidemia and atherogenesis [37]. Others point out the possible relationship with other polymorphisms different from APOE [38]. Besides, many studies are based only on clinical and not pathological criteria. This fact may result in imperfect classification of VaD. Other studies have focused its attention on the possible influence of APOE genotype on white matter hyperintensities seen on magnetic resonance imaging (MRI) in AD and the most of them report no association between allele q4 and white matter changes [30,39 –42]. At the same time, other possible interaction between classical vascular risk factors like arterial hypertension, ischemic cardiopathy, hyperlipemia, stroke, etc. and AD on one side and predisposing factors for AD, like APOE status, female gender, mother’s age at birth, etc. and VaD on
A. Frank et al. / Journal of the Neurological Sciences 203 – 204 (2002) 173–176
the other side, are matters of research. For example, it has been reported that high concentrations of low-density cholesterol lipoprotein are associated with a high risk of dementia with stroke [43]. In our results, the higher percentage of subjects bearing the q4 allele in the AD group compared to the HC group is similar to previous reports and the existing literature of the subject in agreement. Regarding literature controversy about APOE and CVD, our results show no association between CVD or VaD and APOE-4. We conclude that these results support the hypothesis that the APOE q4 allele is a predisposing factor for AD, but not for CVD or VaD. To confirm whether bearing one or two copies of the q4 allele increases susceptibility to cerebrovascular diseases requires a larger prospective study.
[15]
[16]
[17]
[18]
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