Association of the apolipoprotein E epsilon4 allele with late-onset depression.

Apolipoprotein E (ApoE) phenotyping was determined in 42 subjects with Alzheimer's disease (AD), 49 with depression, including 26 with early-onset depression (EOD) and 23 with late-onset depression (LOD), and 49 controls. In the EOD group, the frequency of the ApoE epsilon4 allele was not different from the control frequency (p = 0.532) but was significantly lower than in AD (p < 0.001). In the LOD group, the ApoE epsilon4 frequency was significantly higher than in the controls (p = 0.034) but was not different from that in the AD group (p = 0.229). Individuals with ApoE epsilon4 were at greater risk of getting AD (odds ratio, OR = 5.5, 95% confidence interval, CI, 2.0-14.0) or LOD (OR = 6.1, 95% CI, 1.9-19.0) than of EOD (OR = 0.7, 95% CI, 0.2-2.5). These results suggest an association between the ApoE epsilon4 allele frequency and LOD. Patients with LOD could be at risk of developing AD by an epsilon4-dependent pathway.     

Apolipoprotein E epsilon 4, other risk factors, and course of Alzheimer's disease.

BACKGROUND: The epsilon 4 allele of apolipoprotein E (apoE epsilon 4) is associated with late-onset Alzheimer's disease (AD), but its relationship to various aspects of AD has become increasingly unclear. We studied the relationship of apoE genotype in AD to educational attainment, history of heart disease or head injury, age of onset, gender, severity of illness, depression, psychotic symptoms, rate of dementia progression, and time from initial evaluation to nursing home placement. METHODS: ApoE epsilon 4 genotype was determined for 97 clinically diagnosed AD patients and 61 neuropathologically confirmed cases of AD. RESULTS: Presence of one or more epsilon 4 alleles occurred in 66% of AD cases as compared with 27% in control subjects (allele frequency was .40 for AD, .15 for control subjects). Among AD subjects there was no significant relationship between epsilon 4 alleles and educational attainment, history of heart disease, head injury, age of onset, severity of illness, depression, history of depression, rate of dementia progression, or time to nursing home placement. Marginal correlations emerged between number of epsilon 4 alleles, and delusions (p = .05) and hallucinations (p = .05). There was a trend toward increased epsilon 4 homozygosity in patients with onset between ages 65 and 70 years. CONCLUSIONS: We did not find that individuals with one or two apoE epsilon 4 alleles differed significantly in clinical course of AD from those without epsilon 4 except for a trend toward increased psychotic symptoms in the group as a whole and an increase in epsilon 4 homozygosity in patients with reported symptom onset in the late 60s.     

Decreased cerebrospinal fluid acetylcholinesterase in patients with subcortical ischemic vascular dementia

The main objective was to investigate the acetylcholinesterase E (AChE) activity in the cerebrospinal fluid (CSF) of patients with three common dementia disorders. We also wanted to investigate the influence of apolipoprotein E (ApoE) epsilon4 allele possession and CSF-tau level on the CSF-AChE activity in these patients. The study included 17 consecutive patients with subcortical vascular dementia (SVD), 39 with Alzheimer's disease (AD), 14 with frontotemporal dementia (FTD) and 12 controls. CSF was obtained by lumbar puncture and CSF-AChE activity was measured by an enzyme antigen immunoassay. CSF-AchE activity was significantly decreased compared to controls only in the SVD group (p = 0.010). The CSF-tau level was increased in the AD group compared to the control (p < 0.01) and FTD groups (p < 0.05). No influence of ApoE epsilon4 allele possession on CSF-AChE activity was found. It is suggested that abnormal CSF-AChE activity in patients with SVD reflects a disturbance in the cholinergic system.     

Age-dependent decline in the apolipoprotein E level in cerebrospinal fluid from control subjects and its increase in cerebrospinal fluid from patients with Alzheimer's disease

In order to address the significance of apolipoprotein E (apoE) in the pathogenesis as well as the clinical diagnosis of Alzheimer's disease (AD), we measured its level in cerebrospinal fluid (CSF) from randomly selected Japanese control subjects at various ages (n = 36), which included 14 age-matched controls, and from AD patients including early-onset (n = 11, EOAD) and late-onset (n = 14, LOAD) cases. The CSF apoE level in controls linearly decreased during aging to over 80 years (r(2) = 0.323, p < 0.0001). The CSF apoE level in AD patients was 31.9% elevated compared to the age-matched controls (n = 14, p < 0.05) and linearly increased with a decrement of the patients' Mini Mental State Examination scores. Moreover, the CSF apoE level of EOAD patients (n = 11) was higher than that of LOAD patients (n = 14, p < 0.05), whose APOE epsilon4 allele frequency was significantly higher than that of controls (chi(2) = 7. 16, p < 0.03). Two-dimensional gel electrophoretic analysis of the heparin-Mn(2+)-precipitable lipoprotein fraction in CSFs showed that the ratio between the level of CSF apoA-I and that of CSF apoE of controls was significantly higher than those of all AD and LOAD subjects (p < 0.01, p < 0.05), while the CSF apoA-I-to-apoE ratios of the two AD groups were not significantly different. These results suggest that overproduction of apoE protein may be a consequence of astroglial response to neurodegeneration in AD and that the determination of CSF apoliprotein levels serves as a clinical marker for monitoring the progression of AD.     

Apolipoprotein E phenotypes in healthy normal controls and demented subjects with Alzheimer's disease and vascular dementia in Mie Prefecture of Japan

In order to clarify the association between apolipoprotein E4 (ApoE4) and the pathogenesis of Alzheimer's disease (AD), we analyzed the distribution of the apolipoprotein E (ApoE) phenotypes and the frequency of the apo E alleles epsilon2, epsilon3, and epsilon4 in Japanese healthy controls (n = 1090, an average age of 51.2+/-12.6 years) and demented patients (n=103, mean age of 73.6+/-9.2 years). Demented subjects were divided into three subgroups: early-onset AD group (EOAD; n=25, mean age 63.0+/-6.2 years), late-onset AD group (LOAD; n=33, mean age 79.3+/-5.1 years), and vascular dementia group (VD; n=45, mean age 75.3+/-8.0 years). The apolipoprotein E phenotype was determined by isoelectric focusing and immunoblotting. There were no significant differences in the distribution of the apo E phenotypes by gender or age, and the estimated frequencies of epsilon2, epsilon3 and epsilon4 were 0.05, 0.86 and 0.09, respectively, in the normal controls. There was a significant difference in the distribution of the apo E phenotypes between LOAD and elderly controls aged more than 65 years (P<0.0001). The distribution of the apo E phenotypes in EOAD was the same as that in LOAD. The frequency of the epsilon4 allele was significantly higher in LOAD (0.35, P<0.0001) and EOAD (0.28, P<0.0001) than that in the control subjects (0.07), but not in VD (0.12, P=0.1630). The present findings suggest that ApoE4 is related with both EOAD and LOAD, but not with VD, and support the hypothesis that it is a genetic risk factor of AD.     

Apolipoprotein E gene polymorphism in Indian patients with Alzheimer's disease and vascular dementia

The association of apolipoprotein E (ApoE) gene polymorphism with Alzheimer's disease (AD) has been reported in several populations including one from a rural community in North India. However, the association of ApoE polymorphism with vascular dementia (VaD) is yet to be established in this population. In a case-control study involving 54 cases of dementia (29 AD and 25 VaD) and 76 age-matched healthy controls, the frequency of epsilon4 allele was significantly higher among cases of AD and VaD compared with controls (p < 0.001). The epsilon3epsilon3 (p < 0.05) and epsilon2epsilon3 (p < 0.001) genotypes were found to be protective. The odds of developing AD or VaD were 4.4 and 3.7 times higher, respectively, in the presence of even a single epsilon4 allele. Our results suggest that the increased risk of developing AD or VaD is similar among Asian Indians with ApoE epsilon4 compared with the Caucasian population.     

Apolipoprotein E epsilon4 allele frequency in elderly depressed patients with and without cerebrovascular disease

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) epsilon4 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 epsilon4 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 epsilon4 allele frequency showed significant differences between: AD group and the vascular LOD and NC groups; LOD group without CVD compared with NC group (p<0.05 to 0.001). The frequency of the epsilon4 allele in the LOD group without CVD did not differ significantly from the AD group, similarly the frequency of the epsilon4 allele in the vascular LOD group was not different from that in NC. The study suggests an association between the ApoE epsilon4 allele and the LOD without CVD. These patients could be at risk of developing AD by an epsilon4-dependent pathway. In contrast, the results show no association between the presence of ApoE epsilon4 allele and vascular depression and provide further evidence in support of the concept that ApoE epsilon4 allele is not associated with clinical CVD.     

The -491AA polymorphism in the APOE gene is associated with increased plasma apoE levels in Alzheimer's disease

Recent evidence suggests that a polymorphism in the regulatory region of the apolipoprotein E gene (APOE) is associated with an increased risk for developing Alzheimer's disease (AD) independent of that conveyed by the epsilon4 allele of APOE. Previous work by our group indicated that plasma apolipoprotein E (apoE) levels were elevated in AD, raising the possibility that the -491 genotype might modify AD risk by increasing expression of the APOE gene. In a total of 638 individuals the -491AA genotype was significantly associated with AD (P < 0.005) while the TT genotype was associated with controls (P < 0.005). In 138 individuals the AA genotype showed significantly higher plasma apoE levels, independent of epsilon4 and AD status (P < 0.01) as well as within control and AD groups (P < 0.05). Within the AD group the AA genotype showed increased apoE levels when compared to AA controls (P < 0.0001). These results suggest that the -491 AA genotype is associated with increased plasma apoE levels, providing a potential basis for elucidating how that genotype increases the risk for developing AD.     

Cerebral β-amyloid deposition is augmented by the –491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E ε4 allele

The apolipoprotein E epsilon4 allele (APOE, gene; apoE, protein) is widely accepted as a risk factor for Alzheimer's disease (AD). Our previous studies found that APOEepsilon4 promotes AD pathogenesis by fostering the early deposition of the amyloidogenic peptide Abeta in the aging brain. Recent reports suggest that polymorphisms in the upstream promoter region of APOE differentially affect the production of apoE and also may have an important influence on the probability of developing AD. In this study, we asked whether APOE promoter -491 (A/T) variants interact with APOE polymorphisms to modulate the degree of beta-amyloid- and tau-related pathology in the medial temporal lobe of the non-demented elderly. Our results confirm that APOEepsilon4 is associated with increased formation of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles in the medial temporal lobe. We also found that homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with increased Abeta17-24 and Abeta42 deposition in APOEepsilon4-positive cases, but not in cases lacking the epsilon4 allele. In comparison, Abeta burden is significantly less in epsilon4 carriers with the -491AT and -491TT promoter allelotypes. There was no effect of -491 polymorphisms on Abeta40 deposition (which is relatively sparse in the non-demented elderly), on the number of activated microglia, or on the amount of neurofibrillary tangles. We conclude that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the APOE promoter that enhance apoE production.     

Involvement of apolipoprotein E in multiple sclerosis: absence of remyelination associated with possession of the APOE epsilon2 allele

Lipids are a major constituent of myelin and apolipoprotein E (apoE) plays a key role in lipid transport. We therefore hypothesized that apoE is involved in the processes of demyelination and remyelination. Furthermore as there is a biologically significant polymorphism in the APOE gene, the APOE genotype may influence the course of multiple sclerosis (MS). Specifically, as there is reduced affinity of the apoE E2 isoform for receptors on glial cells, we hypothesized that remyelination is impaired in individuals with the apoE epsilon2 allele. We determined the apoE genotypes of 71 archival cases of multiple sclerosis and 41 controls, reviewed the neurohistology, and performed apoE immunohistochemistry. ApoE immunoreactivity was increased in demyelinated areas compared with control white matter. ApoE immunostaining was markedly increased in areas of active demyelination, specifically in macrophages and astrocytes. The APOE allele frequencies of the cases of MS (epsilon2 = 0.06, epsilon3 = 0.8, epsilon4 = 0.13) resembled those of controls. Evidence of remyelination was identified in 25/ 71 MS cases (35%): in 25/64 patients (39%) without an epsilon2 allele and 0/7 (0%) patients with an epsilon2 allele (p < 0.05). In conclusion, we provide evidence that apoE is involved in the trafficking of lipid in MS and, although the number of cases with this allele was small, remyelination may be defective in patients with the APOE epsilon2 allele.     

Apolipoprotein E in Taiwan Chinese patients with dementia

To clarify whether Alzheimer's disease (AD) and vascular dementia (VaD) share the same risk factors in Taiwan Chinese patients. Using the criteria of the NINCDS- ADRDA and NINDS-AIREN, 154 AD patients, 30 VaD patients, and 112 controls were enrolled. Their apolipoprotein E (ApoE) genes, extracted from peripheral blood leukocytes, were analyzed. The epsilon4 allele frequency was significantly higher in AD patients than in the control group. The odds ratio of carrying at least one copy of the epsilon4 allele in AD patients is 2.7 compared with control subjects. There was no significant difference between the VaD patients and the control subjects in their ApoE epsilon4 or epsilon2 allele frequency. The present study demonstrates a strong association between the ApoE epsilon4 allele and AD, but not between the ApoE epsilon4 allele and VaD. This suggests that AD and VaD do not share the same pathogenesis and deserve further investigation.     

Apolipoprotein C-I Expression in the Brain in Alzheimer's Disease

The H2 allele of apolipoprotein (apo) C-I is associated with Alzheimer's disease (AD). However, this association is potentially confounded by the linkage disequilibrium of H2 with the epsilon2 and epsilon4 alleles of apoE and of H1 with the epsilon3 allele. To establish plausibility for a direct role for apoC-I in AD, we compared apoC-I and apoE protein and mRNA levels in postmortem specimens of frontal cortex and hippocampus from AD patients with levels in nondemented controls. In H2-allelic individuals (usually also epsilon4 carriers), apoC-I mRNA levels were strikingly lower with AD (by 65%, P < 0.05), but apoC-I protein levels in AD were significantly higher (by 34%, P < 0.05). The opposite direction of the apoC-I mRNA and apoC-I protein level changes in AD in the epsilon4/H2 genotype may reflect decreased clearance of CNS lipoproteins associated with apoE4. In H1/H1 (usually epsilon3/epsilon3) individuals, both apoC-I protein and mRNA were lower in AD. ApoC-I protein levels in hippocampus were nearly twice those in frontal cortex. Immunohistochemistry of hippocampus revealed colocalization of apoC-I protein with the astrocytic marker GFAP. In addition, cultured human astrocytes expressed the mRNA for apoC-I. This study confirms apoC-I expression in the CNS and identifies astrocytes as the source of apoC-I. In addition, it has revealed differences in apoC-I expression based on site, genotype, and disease status that may reflect a role for apoC-I in the pathogenesis of AD.     

脑血管病患者载脂蛋白E基因多态性分析

目的 探讨脑血管疾病患者的载脂蛋白E（ApoE）基因多态性。方法 应用聚合酶链式反应——限制性片断长度多态性（PCR-RFLP）技术检测脑血管病患者98例（脑梗死78例，脑出血20例）和90名健康对照的ApoE基因多态性分布特征。应用酶比色法检测血脂水平。结果 脑梗死组E3/4基因型频率及E4等位基因频率显著高于对照组（23.1%&#8197;vs&#8197;7.8%；14.7%&#8197;vs&#8197;5.0%，P均＜0.05）；而E3/3基因型频率及E3等位基因频率显著低于对照组（56.4%&#8197;vs&#8197;78.9%；75.6%&#8197;vs&#8197;88.3%，P均＜0.05）。脑出血组的ApoE基因型及等位基因频率与对照组比较差异无统计学意义（P＞0.05）。不同ApoE基因型之间总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）水平差异有统计学意义（P＜0.05）。结论 ApoE4等位基因是脑梗死发病的遗传易患因子，而ApoE3等位基因则对脑梗死具有保护作用。ApoE基因多态性影响血脂水平。     

Association between apolipoprotein E epsilon4 allele and apathy in probable Alzheimer's disease

OBJECTIVE: There have been inconclusive results to date on the association between the Apolipoprotein E (ApoE) genotype and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). We investigated whether ApoE epsilon4 allele is associated with NPS in probable AD. METHOD: Data for 197 subjects with probable AD were analysed. The Neuropsychiatric Inventory was used to evaluate the frequency and severity of NPS. Multiple logistic regression models were used to test the association between ApoE genotype and NPS in AD. RESULTS: The ApoE epsilon3/3 genotype was present in 52.3%, epsilon3/4 in 44.1%, and epsilon4/4 in 3.6% of patients. ApoE epsilon4 carriers showed a higher frequency of apathy than non-carriers. After multiple adjustments, the ApoE epsilon4 allele was significantly associated with apathy. CONCLUSION: Our results suggest a relationship between the ApoE epsilon4 allele and apathy in patients with AD.     

Age-dependent association of apolipoprotein E genotypes with stroke subtypes in a Japanese rural population

BACKGROUND AND PURPOSE: The association between apolipoprotein E (apoE) polymorphisms and stroke has been controversial. These controversies may be due to inaccurate classification of stroke and differences in age ranges. We investigated the association between apoE genotypes and stroke subtypes (confirmed by CT or MRI findings) by case-control study in a Japanese rural population. METHODS: First-ever-stroke patients (n=322; cerebral infarction, n=201, intracerebral hemorrhage, n=84, and subarachnoid hemorrhage, n=37) aged 40 to 89 years were recruited from Hokuetsu Hospital, Japan. Healthy controls (n=1126) were selected from the general population in the same area. ApoE genotypes were determined by restriction fragment-length polymorphism analysis. RESULTS: Compared with apoE epsilon3/epsilon3 subjects, epsilon2 carriers had a 2-fold risk of cerebral infarction (OR 1.9, 95% CI 1.1 to 3.2). Among cerebral infarction patients, epsilon2 carriers had increased risks of cortical infarction (OR 2.4, 95% CI 1.3 to 4.6) (an anatomic subtype) and atherothrombosis (OR 3.9, 95% CI 1.7 to 9.0) and cardioembolism (OR 4.9, 95% CI 1.6 to 14.4) but not lacunar infarction (clinical subtypes). ApoE epsilon4 carriers had a 2. 5-fold risk of subarachnoid hemorrhage (OR 2.5, 95% CI 1.1 to 5.4). ApoE epsilon2/epsilon2 subjects had an increased risk of intracerebral hemorrhage (OR 4.4, 95% CI 1.0 to 19.7). ApoE epsilon3/epsilon4 subjects showed approximately 2-fold increased risk of atherothrombosis (OR 2.1, 95% CI 1.0 to 4.1) and intracerebral hemorrhage (OR 1.8, 95% CI 1.0 to 3.3). The association between epsilon2 and stroke was accentuated in subjects aged 70 years or older but not in those aged 40 to 69 years. CONCLUSIONS: Our study suggests that apoE epsilon2 is a risk factor for atherothrombosis, cardioembolism, and intracerebral hemorrhage, whereas epsilon4 is a risk factor for atherothrombosis, intracerebral hemorrhage, and subarachnoid hemorrhage. The occurrence of stroke may be affected by interaction between age and apoE gene polymorphisms.     

Absence of Association of α1-Antichymotrypsin Polymorphisms with Alzheimer's Disease: A Report on Autopsy-Confirmed Cases

α₁-Antichymotrypsin (ACT) polymorphisms were examined in 79 cases with autopsy-confirmed Alzheimer's disease (AD) as well as in 28 cases with autopsy-confirmed nonneurological diseases to test the hypothesis that ACT polymorphisms confer a risk to an individual to develop AD. Neither ACT genotype frequency nor ACT allele frequency in the AD group was significantly different from the control group. The ACT polymorphic pattern was essentially the same among apolipoprotein E (apoE) ?4 carriers and noncarriers. The age at onset of AD was not significantly affected by the inherited dose of ACT/A allele. Taking together, our observations do not confirm the effect of the ACT/A allele as a risk factor for developing AD in addition to the ApoE ?4 allele.     

上海市社区人群阿尔茨海默病与载脂蛋白E基因的关联分析

目的探讨上海地区社区老年人群中阿尔茨海默病(AD)与载脂蛋白E(ApoE)ε     

Apolipoprotein E polymorphism and central nervous system tumors: correlation with cell proliferation indices and clinical outcome

AIMS: This study was designed to determine whether the polymorphism of apolipoprotein E (apoE), one of the key regulatory proteins in cholesterol metabolism, is related to varying susceptibility to central nervous system (CNS) neoplasms, and to evaluate any possible interaction between this polymorphism and tumor cell proliferation or clinical outcome. METHODS AND RESULTS: 53 CNS tumors were selected. Follow-up and survival data were available for 36 patients. ApoE genotypes and cell proliferation indices (nucleolar organizer regions, MIB-1, PCNA, p53) were determined from paraffin-embedded tissue by standard methods. Each of the indices of cell proliferation correlated positively with tumor grade and negatively with duration of clinical follow-up and survival. There was a non-significant trend for apoE epsilon2 allele carriers to have high-grade tumors and apoE epsilon4 allele carriers to have low-grade tumors. Possession of apoE epsilon4 was associated with a more advanced age of disease presentation (p < 0.01) and a longer duration of follow-up (p < 0.04). No significant correlations were found between possession of either apoE epsilon2 or apoE epsilon4 alleles and indices of cell proliferation. CONCLUSIONS: These preliminary findings suggest that possession of apoE epsilon4 allele may correspond to a more favorable clinical course in terms of more advanced age of disease presentation, and longer duration of follow-up and survival in patients with CNS neoplasms.