Apolipoprotein E phenotype in demented patients in Greek population

Apolipoprotein E is a plasma protein, involved in the transport of lipids and their metabolism. The aim of this investigation was to correlate the ApoE phenotypes with the type and the severity of dementia in Greek demented patients. The investigation revealed that 72% of the patients have the E3/3 phenotype, but only 11% of them demonstrated the E3/2; 13% of the patients have the E4/3 phenotype and only 4% of them demonstrated the phenotype E4/4. The most severely demented patients corresponded to e4 alléle. The present results indicate that the most common ApoE phenotype in Greek demented patients is E3/3.     

Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease

Controversy exists regarding the apolipoprotein E (ApoE) epsilon4 allele association with vascular dementia (VaD), ranging from increased epsilon4 frequency, similar to that found for Alzheimer's disease (AD), to no association between the epsilon4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE epsilon4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE epsilon4 allele-bearing individuals had greater risk of having late-onset AD (OR = 8.8; 95% CI 3.7-21.0), or non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0).     

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.     

Astrogliosis and the ApoE genotype. an immunohistochemical study of postmortem human brain tissue.

Significantly increased glial fibrillary acidic protein (GFAP) expression was seen in postmortem brain tissue from demented patients with Alzheimer's disease (AD) (73 cases, 61 females/12 males, mean age 84 +/- 9 years) compared to controls (22 cases, 10 females/12 males, mean age 78 +/- 9 years). In demented patients, the GFAP expression, counts of AD lesions, senile/neuritic plaques (SP/NP) and neurofibrillary tangles (NFT) were higher in patients carrying the apolipoprotein E (ApoE) epsilon4 allele compared to those without the ApoE epsilon4 allele. The astrogliosis correlated significantly with the counts of NFT in demented patients both with and without the ApoE epsilon4 allele. Furthermore, the astrogliosis correlated significantly with the counts of SP/NP, but this correlation, however, was influenced by the ApoE epsilon4 allele, being significant only in those cases without the ApoE epsilon4 allele. Our results demonstrate that not only the extent of AD lesions and GFAP expression, but also the relationship between AD lesions and the GFAP expression is influenced by the ApoE epsilon4 allele.     

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.     

Apolipoprotein E in patients with dementia of the Alzheimer type and vascular dementia

The phenotypes of apolioprotein E (ApoE) in the plasma of patients with dementia of the Alzheimer type (DAT) and vascular dementia (VD) were determined by the isoelectric focusing method. The ApoE mRNA level in the skin fibroblasts was also determined by the Northern blot analysis. As compared with the control subjects, the frequency of the ApoE ε4 allele was significantly higher in the DAT group as well as the VD group, but was not significantly different in the cerebrovascular disease without dementia (CVD) group. The skin fibroblast ApoE mRNA level in the DAT group and the VD group was significantly lower than that in the control group. These findings suggest that the phenotype of ApoE is associated with DAT and VD, and that the lower level of ApoE mRNA may play an important role in the development of DAT as well as VD.     

The apolipoprotein E epsilon4 allele and the response to tacrine therapy in Alzheimer's disease.

The objective of our study was to evaluate the effects of the apolipoprotein E (ApoE) phenotype and gender on the response to tacrine treatment in Alzheimer's disease (AD). ApoE phenotyping was performed on 76 patients treated with tacrine for AD. This group comprised 33 ApoE epsilon4 allele carriers (epsilon4+) and 43 non-epsilon4 carriers (epsilon4-). Patients were treated blindly in relation to the ApoE phenotype, with incremental tacrine dosages ranging from 40 mg/day up to the highest dosage (160 mg) tolerated without side-effects. At least 6 weeks elapsed between each increase. Changes in the scores for the Alzheimer Disease Assessment Scale-Cognitive Component (ADAS-Cog) between baseline and each increment in dosage were assessed in the epsilon4- and epsilon4+ groups. The cut-off point for being considered as responsive to tacrine treatment was a 4-point decrease in the ADAS-Cog score. There was no tendency for the epsilon4- carriers to respond better than the epsilon4+ carriers. When patients were stratified by gender, no differences were found between the effects of the treatment on men and women. Consequently, these results do not support the hypothesis that the ApoE phenotype and gender are predictors of the response to tacrine in AD patients.     

A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease

Cathepsin D (catD) is an intracellular acid protease possibly involved in Alzheimer's disease (AD)-related neurodegeneration through cleavage of amyloid precursor protein into amyloidogenic components. We studied whether an exonic polymorphism of the catD gene (C --> T [Ala --> Val] transition at position 224), which possibly influences pro-catD secretion and intracellular maturation of the enzyme, was associated with the risk for the development of AD in 127 demented patients and 184 controls. The catD*T allele was significantly overrepresented in demented patients (11.8%) compared with nondemented controls (4.9%). Carriers of the catD*T allele had a 3.1-fold increased risk for developing AD than noncarriers. Carriers of the apolipoprotein E (ApoE) epsilon4 allele (ApoE*4) had a 3.9-fold increased risk than non-carriers. The adjusted odds ratio for subjects with the ApoE*4 and the catD*T allele was 19.0 compared with subjects with neither of these two alleles. Our data confirm the results of a recently performed pilot study in an independent sample and suggest that the catD genotype is strongly associated with the risk for 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。     

Impact of ApoE genotypes variations on Toxoplasma patients with dementia

BackgroundToxoplasma deprives host neuron cells from cholesterol and leads to its ability to potentiate dementia. ApoE intermediates neuronal transmission of cholesterol, which is a key constituent for axonal development, redesigning occasions that are important for education and synaptic arrangement, development of memory and repair of neuron. The aim of this work is to investigate the effect of ApoE genotypes on dementia associated with neurodegeneration in latent Toxoplasma gondii in elderly population.MethodsThis study comprised: 133 patients with dementia (78 were positive for toxoplasma IgG and 55 were negative) and 95 subjects as control group without dementia (30 were positive for toxoplasma IgG and 65 were negative). All of them were subjected to a cognitive assessment, T. gondii seropositivity (ELISA) and determination of ApoE allelic forms (PCR).ResultsThe ApoE genotype distribution shows that the most predominant genotype is ApoE3/3 and the most widely recognized allele is E3. Both patients and control were further divided into Toxoplasma IgG positive group (n = 108) and Toxoplasma IgG negative group (n = 120). ApoE4 non carrier, ApoE 2/3 and ApoE 3/3 alleles have highly significant differences (P < 0.001) between dementia and non-dementia patients in Toxoplasma infected patients in comparison to non-infected ones.ConclusionToxoplasma positive patients have more risk to develop dementia regardless ApoE4 carriage.     

Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease

T. C. Dickson, H. L. Saunders and J. C. Vickers (1997) Neuropathology and Applied Neurobiology , 23, 483–491
Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease
Although the inheritance of certain apolipoprotein E (ApoE) alleles has been recognized as a genetic risk factor for Alzheimer's disease, the role of ApoE in the pathology underlying this disease is unclear. Several reports have emphasized the association of ApoE with either β-amyloid plaque formation or the development of neurofibrillary pathology. Utilization of multiple label immunohistochemical methods enabled us to examine directly the localization of ApoE immunoreactivity relative to β- amyloid plaques, dystrophic neurites and neurofibrillary tangles. In Alzheimer's disease cases, β-amyloid plaques showing high ApoE immunoreactivity were localized to layers II, III and V of the neocortex. In layer I, β-amyloid plaques were unlabelled for ApoE relative to β-amyloid. Dense core plaques labelled for β-amyloid often had only the central portions labelled for ApoE. Conversely, ApoE labelled spherical structures within some plaques were not immunoreactive for β-amyloid or dystrophic neurite markers. Unlike β-amyloid labelled plaques, all ApoE immunoreactive plaques were associated with dystrophic neurites. In preclinical Alzheimer's disease cases, most plaques were double labelled for β-amyloid and ApoE. ApoE did not label dystrophic neurites or the early stages of neurofibrillary tangle formation, indicating that ApoE may not be directly involved in neurofibrillary pathology. The specific presence of ApoE in plaques associated with dystrophic neurites in demented patients suggests that ApoE may contribute toward a higher degree of β- amyloid fibrillogenesis, enhancing the ability of certain plaques to cause damage to surrounding axons.     

Apolipoprotein E genotype in patients with alzheimer's disease: Implications for the risk of dementia among relatives

Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the ?4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack ?4 and many persons having ?4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first-degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of ?4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one ?4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of ?4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one ?4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex-modification effect of the E4 isoform on disease susceptibility.     

HIGH PROPORTION OF DEMENTIA WITH LEWY BODIES IN THE POSTMORTEMS OF A MENTAL HOSPITAL IN GERMANY

Objective. Dementia with Lewy bodies (DLB) is under-recognized in Germany. No data on the number of patients suffering from this condition in Germany are available at present. We were interested in the proportion of DLB in the postmortems of demented inpatients in the care of a psychogeriatric service. Design. In a retrospective study we examined consecutive postmortems of inpatients who died in one mental hospital. Setting. A suburban and rural old age psychiatry service in Germany. Patients. 103 consecutive postmortems had been performed from 9/1987 to 6/1995. Fifty-nine (57.3%) of all cases warranted the clinical diagnosis of dementia (DSM-III-R). Measures. The causes of dementia were examined histologically. Lewy bodies (LBs) were detected with ubiquitin immunohistochemistry. Results. DLB was the third most frequent cause of dementia (13.6% of demented), after dementia of Alzheimer's type (DAT) (35.6%) and mixed DAT and vascular dementia (15.3%), but ahead of ‘pure’ vascular dementia (MID). The DLB group showed a male preponderance compared with the DAT, MID and mixed group of our series. The DLB patients died younger than the DAT patients. The differences, however, were not statistically significant. All DLB cases showed neurofibrillary and amyloid pathology sufficient to warrant an additional diagnosis of DAT. Cases with ‘pure’ LB pathology had not been detected in our series. Conclusions. Our results indicate that by using appropriate methods, ie ubiquitin immunohistochemistry, a considerable number of DLB cases can be detected in postmortems of demented patients from German mental hospitals. © 1997 by John Wiley & Sons, Ltd.     

Fall-related brain injuries and the risk of dementia in elderly people: a population-based study.

Severe head injury in early adulthood may increase the risk of dementia in older age, but it is not known whether head injury in later life also increases the risk of dementia. A representative sample (82%) of persons aged 70 years or older with a Mini-Mental State Examination (MMSE) test score of > or =26 (n = 325) were followed-up for 9 years to record all their fall-related head injuries resulting in traumatic brain injury (TBI). At the end of the follow-up period, 152 persons (81% of the surviving population) were examined for clinical dementia, according to DSM-IV criteria. Eight persons sustained a TBI and 34 developed dementia. Brain injury was associated with younger age at detection of dementia even when adjusted for sex and educational status (low educational status significantly associated with dementia); age-specific hazard ratio (95% confidence interval) 2.80 (1.35-5.81). In a population scoring > or =28 points in the baseline MMSE an apolipoprotein E (ApoE) epsilon4 phenotype was also associated with younger age at the time of detecting dementia; 3.56 (1.35-9.34), and the effect of brain injury and ApoE epsilon4 phenotype was synergistic; 7.68 (2.32-25.3). We conclude that fall-related TBI predicts earlier onset of dementia and the effect is especially high amongst subjects who carry the ApoE epsilon4 allele.     

Apolipoprotein E phenotype alone does not influence survival in Alzheimer's disease: a population-based longitudinal study

Apolipoprotein E4 (ApoE4) phenotype is a known risk factor for development of Alzheimer's disease (AD). Contradictory results exist concerning the role of ApoE4 in the rate of decline and mortality in AD. Conflicting findings have also been reported about ApoE and gender interactions with respect to survival. We examined the survival of subjects with AD and non-AD controls with respect to ApoE phenotype and gender in a population-based longitudinal study. Cognitive evaluation was performed for a total of 980 subjects (then aged 69-78 years), and 48 cases with AD were identified. ApoE4 phenotype was more frequently present among subjects with AD. In the whole study population, survival was not related to the presence of AD or ApoE4 phenotype. Risk of death was increased for men compared to women, independently of the ApoE4 phenotype (HR 0.5, 95% confidence interval 0.44-0.69). In subjects with AD, the presence of ApoE4 alone did not influence survival. However, in the AD group, ApoE4-negative men had significantly increased risk of mortality compared to the risk in ApoE4-negative women (p < 0.01). We conclude that the presence of ApoE4 phenotype or AD did not influence mortality in the aged population. Once AD had become manifest, ApoE4 alone did not relate to survival. However, in subjects with AD not carrying ApoE4, men had reduced survival compared to women.     

Antibodies against GM1 in demented patients

The aim of this study was to evaluate the levels of anti-GM1 in demented patients, correlating them with the type and severity of dementia as well as with the eventually coexistent polyneuropathy. Anti-GM1 concentrations were measured in the sera of 33 demented patients with a male-to-female ratio of 1:2.7 (the mean age was 69.7 years for males and 70.1 years for females). Eighty-two percent of the patients revealed increased values of anti-GM1, but only 18.2% demonstrated polyneuropathies. Fifty-nine percent of the patients suffered from vascular dementia. The most severely demented patients demonstrated a Mini-Mental State Examination score of 5 to 23 out of 30 and revealed the most increased levels of anti-GM1 (>40 EU/mL). The findings of this study are indicative of a possible correlation between the levels of anti-GM1 and the severity of dementia, mainly of the vascular type.     

载脂蛋白E基因多态性和脑出血关系的研究

目的:探讨载脂蛋白E基因(ApoE)多态性与脑出血的相关关系。方法:采用病例-对照研究,对313例脑出血患者和351例正常对照组进行研究。采用聚合酶链式反应-限制性片段长度多态性方法测定ApoE基因多态性。结果:脑出血组ApoE基因型频率E3/3、E3/4、E3/2、E2/4、E4/4和E2/2型分别为69.0％、15.00％、11.5％、2.9％、1.0％、0.6％。ApoE各基因型和等位基因频率在脑出血组和对照组之间无显著性差异(P>0.05)。结论:研究未发现ApoE基因多态性与脑出血之间存在相关关系     

Suspected dementia: evaluation of 323 consecutive referrals

A neurological outpatient department studied 323 consecutive referrals for suspected dementia: 135 (41.8%) were not demented. Of the patients 12.1% had diffuse cognitive disorder; 10.2% circumscribed memory disorder; 0.9% other circumscribed cognitive disorder, 14.2% psychiatric disorder, and 4.3% were judged to be normal. Of the nondemented, 44.1% had a potentially treatable cause for their cognitive symptoms; in 27.4% it was depression. The total of demented patients was 188 (58.2%): 38.8% had primary degenerative dementia; 37.2% vascular dementia including combined degenerative and vascular dementia; and 23.4% had a specific cause. Patients with specific cause were significantly younger than those with other causes of dementia. A potentially treatable cause was found in 10.7% of all demented patients, the most common being metabolic disorders, meningioma, hydrocephalus, subdural haematoma, and depressive pseudodementia.     

载脂蛋白E基因多态性和脑梗死关系的研究

目的探讨载脂蛋白E基因(ApoE)多态性与脑梗死的关系.方法采用病例-对照研究,对379例脑梗死患者和351例对照组进行研究.采用聚合酶链式反应-限制性片段长度多态性方法测定ApoE基因多态性.结果脑梗死组ApoE基因型频率E3/3、E3/4、E3/2、E2/4和E4/4型分别为72.3%、14.5%、11.6%、0.8%、0.8%.在脑梗死组中未发现E2/2.E2/2在脑梗死组和对照组之间有显著性差异(P＜0.05.)结论ApoE2/2对脑梗死可能具有保护作用.