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.     

Apolipoprotein E epsilon 4 in an autopsy series of various dementing disorders

Apolipoprotein E (APOE) allele epsilon 4 is a risk factor for Alzheimer's disease (AD) and has also been associated with impaired recovery from brain injury. Previous studies on APOE epsilon 4 in dementing disorders other than AD have been rather conflicting, in particular concerning frontotemporal dementia (FTD) and vascular dementia (VD). In the present study we determined APOE genotype in an autopsy series of demented subjects and non-demented controls from the Netherlands Brain Bank. We attempted to create as clear-cut diagnostic groups as possible and paid close attention to AD-type histopathological changes in all cases. In comparison with the APOE epsilon 4 allele frequency in controls (0.12; n=163 subjects), the APOE epsilon 4 allele frequency was significantly increased in AD (0.42; n=320, p<0.0001), as well as in AD with Lewy bodies (0.43; n=41, p<0.0001) and in demented subjects with no other neuropathological findings than AD-histopathology insufficient for a diagnosis of AD (0.29; n=41, p<0.001). However, the APOE epsilon 4 allele frequency was not significantly increased in FTD (0.18; n=49), VD (0.10; n=20) or in Lewy body disease without concomitant AD changes (0.13; n=12). As concerns dementing disorders, our results suggest that APOE epsilon 4 is selectively associated with the presence of AD-type histopathology.     

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.     

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).     

APOE genotype and hippocampal volume change in geriatric depression.

BACKGROUND: Apolipoprotein E has been associated with hippocampal volume loss in Alzheimer's disease and in elderly controls. In this study, we examined the role of apolipoprotein E and hippocampal volume change in 45 older nondemented depressed subjects. All had baseline and 2-year magnetic resonance imaging scans. METHODS: Hippocampal volumes were determined using a semiautomated method. RESULTS: Compared with 36 depressed subjects without an apolipoprotein E epsilon4 allele, 9 subjects with at least one APOE epsilon4 allele showed significant decline in hippocampal volume, particularly in the right hippocampus. In a logistic model, percent change in right hippocampal volume remained associated with presence of an APOE epsilon4 allele after controlling for age, gender, Mini-Mental State Examination score, and baseline total cerebral volume. CONCLUSIONS: Future studies are needed to explain this association and to determine whether the finding for the right hippocampus has a biological basis, or if it is merely a function of small sample size.     

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 epsilon4 allele affects the relationship between stress and depression in caregivers of patients with Alzheimer's disease

We examined the effect of the apolipoprotein E (apo E) epsilon4 allele on the relationship between self-reported stress and mood in caregivers of patients with Alzheimer's disease. Eighty-six female subjects between the ages of 28 and 82 years who were community-dwelling AD patient caregivers participated in the study. A cross-sectional analysis of stress and mood was performed using the Revised Memory and Behavior Problem Checklist and the Geriatric Depression Scale. All subjects were evaluated for normal cognitive function (Mini-Mental Status Examination) and apo E genotype. The results indicated that increased levels of stress were associated with increased levels of depressive symptoms in nondemented caregivers with the epsilon4 allele. This relationship was not observed in caregivers without the epsilon4 allele. These results suggest that carriers of the epsilon4 allele may respond differently to psychological stress than do individuals without the epsilon4 allele.     

Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study

BACKGROUND: Alleles of the apolipoprotein E (APOE) gene modulate risk for Alzheimer's disease, with carriers of the epsilon4 allele being at increased risk and carriers of the epsilon2 allele possibly at decreased risk compared with non-carriers. Our aim was to determine whether possession of an epsilon4 allele would confer children with a neural substrate that might render them at risk for Alzheimer's disease, and whether carriers of the epsilon2 allele might have a so-called protective cortical morphology. METHODS: 239 healthy children and adolescents were genotyped and had repeated neuroanatomic MRI (total 530 scans). Mixed model regression was used to determine whether the developmental trajectory of the cortex differed by genotype. FINDINGS: Cortical thickness of the left entorhinal region was significantly thinner in epsilon4 carriers than it was in non-epsilon4 carriers (3.79 [SE 0.06] mm, range 1.54-5.24 vs 3.94 [0.03] mm, 2.37-6.11; p=0.03). There was a significant stepwise increase in cortical thickness in the left entorhinal regions, with epsilon4 carriers having the thinnest cortex and epsilon2 carriers the thickest, with epsilon3 homozygotes occupying an intermediate position (left beta 0.11 [SE 0.05], p=0.02). Neuroanatomic effects seemed fixed and non-progressive, with no evidence of accelerated cortical loss in young healthy epsilon4 carriers. INTERPRETATION: Alleles of the apolipoprotein E gene have distinct neuroanatomic signatures, identifiable in childhood. The thinner entorhinal cortex in individuals with the epsilon4 allele might contribute to risk of Alzheimer's disease.     

Case-control study of presenilin-1 intronic polymorphism in sporadic early and late onset Alzheimer's disease

OBJECTIVE: Presenilin-1 is a major causative gene for early onset familial Alzheimer's disease, and the apolipoprotein E epsilon4 allele is a major genetic risk factor known to influence late onset and sporadic early onset Alzheimer's disease. The presenilin-1 1/1 genotype has recently been reported to be associated with sporadic Alzheimer's disease. The purpose of this study is to determine whether Alzheimer's disease is associated with presenilin-1 gene polymorphism and the apolipoprotein E genotype in an extended case-control study. METHODS: An examination was conducted on 217 patients with Alzheimer's disease, along with an equal number of age and sex matched controls derived from the same community in a Japanese population, by using a chi2 test for homogeneity and a logistic regression analysis. A meta-analysis of data from the literature on allele frequencies in Alzheimer's disease and control populations was used for comparison with the Japanese allele frequencies obtained in this study. RESULTS: The presenilin-1 allele-1 frequencies were similar in patients with early onset Alzheimer's disease (0.61) and younger controls (0.61), and in those with late onset Alzheimer's disease (0.63) and elderly controls (0. 63). We found no evidence for a possible association between the presenilin-1 polymorphism and the apolipoprotein E epsilon4 allele. However, the meta-analysis showed that the association between the presenilin-1 1/1 genotype and Alzheimer's disease was significant (Peto odds ratio=1.16, 95% confidence interval=1.04-1.31). CONCLUSIONS: These results suggest a subtle but positive association of presenilin-1 gene polymorphism with Alzheimer's disease, although Japanese data in this study which failed to support such a relation would indicate an ethnic variation.     

Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E epsilon4 allele

Although apolipoprotein E epsilon4 is an established risk factor for Alzheimer's disease, its effect on the rate of progression of Alzheimer's disease remains unknown. The purpose of this longitudinal study was to elucidate whether the rate of hippocampal atrophy is a function of the apolipoprotein E genotypes and severity of disease. Fifty-five patients with probable Alzheimer's disease were the subjects. The annual rate of hippocampal atrophy was determined by using magnetic resonance imaging repeated at a 1-year interval. On a two-way analysis of variance, the effect of the apolipoprotein E epsilon4 allele on hippocampal atrophy was significant, but neither the effect of severity nor the interaction term was significant. In further analysis with one-way analysis of variance, the mean annual rate of hippocampal atrophy was significantly different between the groups of patients with (9.76 +/- 4.27%) and without the apolipoprotein E epsilon4 allele (6.99 +/- 4.24%). Apolipoprotein E epsilon4 dose was significantly correlated with the rate of hippocampal atrophy (rs = 0.277, Spearman rank correlation coefficient), suggesting a gene dose effect. The involvement of the apolipoprotein E epsilon4 allele in the progression of hippocampal atrophy has implications for therapeutic approaches in Alzheimer's disease and should be taken into consideration in longitudinal studies including clinical drug trials.     

The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer's disease.

BACKGROUND AND OBJECTIVES: Apolipoprotein E (apoE) has been implicated in regenerative processes in the brain after trauma, as well as in the pathogenesis of Alzheimer's disease. Inheritance of a specific apo epsilon allele (apo epsilon 4) determines in part the risk and the mean age at onset of Alzheimer's disease. ApoE has been found to bind isoform specifically to beta-amyloid protein, the major component of senile plaques, and to the microtubule associated protein tau, which forms paired helical filaments and neurofibrillary tangles. The aim was to further examine the relation between apo epsilon alleles, especially apo epsilon 4, and the development of neuropathological changes associated with Alzheimer's disease. METHODS: Brains of patients with Alzheimer's disease (n = 44) and vascular dementia (n = 11) and of age matched controls (n = 29) were studied. Senile plaques and neurofibrillary tangles in the hippocampus and frontal cortex were quantified. RESULTS: No correlation was found between the number of apo epsilon 4 alleles and the number of senile plaques and neurofibrillary tangles in the hippocampus or the frontal cortex of patients with Alzheimer's disease, or vascular dementia, or control groups. No significant differences in duration or severity of dementia were found between patients with or. without the apo epsilon 4 allele. No increased frequency of apo epsilon 4 was found in vascular dementia. CONCLUSION AND COMMENT: Although the apo epsilon genotype clearly affects whether Alzheimer's disease will develop or not, the present study suggests that it has no influence on pathology or clinical intellectual status, once the dementia has manifested itself. No increased apo epsilon 4 allele frequency was found in neuropathologically diagnosed patients with vascular dementia in whom concomitant Alzheimer's disease can be excluded.     

Apolipoprotein E ε4 allele distribution in alcoholic dementia and in Alzheimer's disease in Japan

The apolipoprotein E ε4 allele has been associated with both familial and sporadic Alzheimer's disease (AD). Given its possible role in nerve repair and growth, it is plausible that apolipoprotein E may be a common denominator in the pathogenesis of several dementing diseases. Therefore, we investigated ε4 frequencies in demented and nondemented alcoholics, as well as in patients with sporadic AD and controls in Japan. No significant difference in allele frequencies was found between demented and nondemented alcoholics and controls, while a significant association was demonstrated between AD and the ε4 allele. These results support a specific role of ε4 in the pathogenesis of AD, rather than a more general role for ε4 in dementing illnesses.     

APOE-epsilon4 and APOE -491A polymorphisms in individuals with subjective memory loss

The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of certainty in specialized centres. The identification of predictive or diagnostic genetic factors may improve accuracy of disease prediction or diagnosis. One major genetic risk factor, the epsilon4 allele of the apolipoprotein E gene, is universally recognised. We have recently shown that the A allele of the apolipoprotein E, -491A/T promoter polymorphism is also an important risk factor for Alzheimer's disease in an Australian population. We designed the present study to investigate the association between apolipoprotein E genotype, -491A/T polymorphism, plasma apoE levels and the subjective experience of memory decline among 98 subjects and 49 age, gender and education-matched normal controls. An increased frequency of the epsilon4 allele of apolipoprotein E was significantly associated with the 'memory complainers' group (OR = 2.35, P = 0.02) as was the A allele of the -491A/T polymorphism (OR = 2, P = 0.02). Among all subjects, only seven individuals were homozygous for both of these alleles, and six of these seven individuals belonged to the 'memory complainers' group. This sub-group also had relatively elevated plasma apolipoprotein E levels (P < 0.01) and tended to score lower on the Mini-Mental State Examination (MMSE) and Cambridge Cognition Test. These data suggest that the epsilon4 allele of apolipoprotein E and the -491A allele are over-represented among individuals who complain of memory difficulties. Follow-up studies should clarify whether these genotypes and phenotypes are useful in the prediction and/or diagnosis of Alzheimer's disease.     

Lack of genetic associations of alpha-1-antichymotrypsin polymorphism with alzheimer-type neuropathological changes or sporadic Alzheimer's disease.

To elucidate the influence of the alpha1-antichymotrypsin (ACT) polymorphism on Alzheimer-type neuropathological changes and the development of sporadic Alzheimer's disease (AD), we studied the relationship between the ACT polymorphism and the severity of Alzheimer-type neuropathological changes in the brains from AD patients and nondemented subjects. There was no association of the ACT polymorphism with Alzheimer-type neuropathological changes in AD or nondemented individuals. ACT polymorphism was not associated with the development of AD. These results remained nonsignificant when the ACT genotype groups were divided into subgroups according to the apolipoprotein E (ApoE) epsiolon4 status. Our study shows that the ACT polymorphism has no effect on Alzheimer-type neuropathological changes or the development of AD, either alone or in combination with ApoE epsiolon4.     

Apolipoprotein E genotype and lipid and lipoprotein levels in dementia

In 64 individuals with dementia (26 Alzheimer type, 34 of vascular origin and 4 other types of dementia) apolipoprotein E genotype was identified. Frequency of epsilon4 allele was 36.5% in Alzheimer patients and 32.4% in vascular dementia ones. In a group of 39 nondemented individuals of the same age the epsilon4 frequency was 11.5%. In demented patients, carriers of epsilon4, a tendency to higher plasma levels of atherogenic lipids (total cholesterol and low-density lipoprotein cholesterol) as compared with noncarriers was observed. It is possible that the epsilon4 form may aggravate the course of dementia through a moderate influence on the atherogenic lipoprotein level. The results showed that both Alzheimer disease and vascular dementia shared the same risk factors which is consistent with current opinion about a link existing between these two types of dementia.     

Down syndrome, Alzheimer's disease and seizures

Neuropathologically, Alzheimer-type abnormalities are demonstrated in patients with Down syndrome (DS), both demented and nondemented and more than a half of patients with DS above 50 years develop Alzheimer's disease (AD). The apolipoprotein E epsilon4 allele, oestrogen deficiency, high levels of Abeta1-42 peptide, elevated expression of BACE2, and valine polymorphism of prion protein gene are associated with earlier onset of dementia in DS individuals. Advanced AD alone may be an important risk factor for new-onset seizures in older adults and age above 60 years is a recognized risk factor for poor outcome from convulsive and nonconvulsive status epilepticus. DS patients aged over 45 years are significantly more likely to develop Alzheimer's disease than those less than 45 years and up to 84% demented individuals with DS develop seizures. Late-onset epilepsy in DS is associated with AD, while early-onset epilepsy is associated with an absence of dementia. In AD patients with a younger age of dementia onset are particularly susceptible to seizures. DS adults with epilepsy score significantly higher overall on the adaptive behaviour profile. Language function declined significantly more rapidly in AD patients with seizures and there is a good correlation between the severity of EEG abnormalities and cognitive impairment whereas in DS slowing of the dominant occipital rhythm is related to AD and the frequency of the dominant occipital activity decreases at the onset of cognitive deterioration.     

The effects of prolonged stress and APOE genotype on memory and cortisol in older adults.

BACKGROUND: Chronic elevations in cortisol associated with prolonged stress have been associated with memory loss, as has the apolipoprotein E gene (APOE-epsilon4) genotype. Combined effects of stress and APOE status on memory and cortisol in humans have not been studied. METHODS: A semistructured interview with standardized scoring was used to measure stress level and univariate analysis of variance to assess effects of stress and APOE-epsilon4 status on memory and salivary cortisol in 91 nondemented subjects (mean age 78.8 years). RESULTS: Low-stress subjects performed better than high-stress subjects on delayed recall of stories (p = .04), word lists (p = .02), and visual designs (p = .04). APOE-epsilon4-negative subjects obtained better scores than epsilon4-positive subjects on immediate (p = < .01) and delayed (p < .01) recall of visual designs. Significant stress by APOE-epsilon4 interaction effects on memory (p = .03) and cortisol (p < .01) resulted from consistently worse memory and higher cortisol concentrations in the high stress, epsilon4-positive group. CONCLUSIONS: These findings are consistent with a model in which prolonged exposure of older, nondemented individuals to stress in the presence of an epsilon4 allele leads to memory decline. Further studies will assess whether stress and APOE-epsilon4 interact to increase the risk of developing Alzheimer's disease.     

APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study

BACKGROUND: Both family aggregation and apolipoprotein E (APOE) epsilon4 allele are well-known risk factors for dementia, but the relation between these two factors remains unclear. OBJECTIVE: To explore whether the risk of dementia and Alzheimer disease (AD) due to a positive family history is explained by APOE genotypes. DESIGN: Community-based cohort study. SETTING: The Kungsholmen district of Stockholm, Sweden. PARTICIPANTS: A total of 907 nondemented people 75 years or older, followed up for 6 years to detect incident dementia and AD cases according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. MAIN OUTCOME MEASURES: Risk of dementia and AD by Cox proportional hazards models after controlling for several potential confounders. RESULTS: Subjects who had at least 2 siblings with dementia were at an increased risk of AD. Individuals with both APOE epsilon4 allele and at least 2 affected first-degree relatives had a higher risk of dementia and AD compared with those without these 2 factors. Similar results were obtained for history of dementia separately in parents or siblings. Among the epsilon4 allele carriers, subjects with 2 or more first-degree demented relatives had increased risk of dementia and AD, whereas no increased risk was detected among non-epsilon4 carriers. CONCLUSIONS: Family history of dementia was associated with an increased risk of dementia and AD in this very old population, but only among APOE epsilon4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE epsilon4 allele.     

Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer's disease.

OBJECTIVES: To determine the association between the epsilon2 and epsilon4 alleles of apolipoprotein E (ApoE) and independent measures of cognitive decline and non-cognitive symptomatology in late onset Alzheimer's disease. METHODS: The frequency of the epsilon2 and epsilon4 alleles of ApoE and their association with measures of cognitive decline and non-cognitive symptomatology were assessed in a population based case register study of 164 patients with late onset Alzheimer's disease from the east Lambeth and south Southwark districts of south London. RESULTS: Analysis of a wide range of non-cognitive symptoms against ApoE epsilon4 genotype showed no significant association but a positive relation was found between ApoE epsilon2 genotype and depressive symptomatology (P = 0.004). No relation was found between measurements of cognitive decline and the presence of the ApoE epsilon4 allele. A trend for decreasing age at onset of 3 to 4 years in carriers of the ApoE epsilon4 allele was found, confirming earlier studies. CONCLUSION: Presence of the epsilon4 allele of ApoE is associated with an earlier age at onset but does not seem to be related to either a more severe psychopathology or a more rapid progression of the illness. The epsilon2 allele of ApoE is associated with depressive symptomatology in late onset Alzheimer's disease.     

Apolipoprotein E genotype and noncognitive symptoms in Alzheimer's disease.

BACKGROUND: The apolipoprotein E (ApoE) epsilon 4 allele confers significant risk for Alzheimer's disease and is associated with a greater amyloid burden in the brain. Future treatments may target molecular mechanisms associated with this allele, and it is important to define any phenotypic characteristics that correspond to this genotype. We sought to clarify the relationship between ApoE status and noncognitive symptoms in Alzheimer's disease patients. METHODS: Possible and probable Alzheimer's disease patients from a clinical trial (n = 605) were assessed with the 10-item Neuropsychiatric Inventory cross-sectionally prior to treatment, and their ApoE genotype was determined. Among the population studied, the following numbers with specific genotypes were studied: 23-2/3, 17-2/4, 209-3/3, 288-3/4, 68-4/4. RESULTS: When correlations were controlled for the patient's level of cognitive impairment, there was no relationship between epsilon 4 dose and any of the 10 noncognitive symptoms assessed, including psychosis, mood changes, and personality alterations. CONCLUSIONS: Among patients with comparable disease severity, the epsilon 4 allele does not confer additional psychiatric morbidity.