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 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.     

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 and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia

Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and alpha(1)-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer's disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE epsilon 4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE epsilon 2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE epsilon 4 and AD and indicate an increase in ApoE epsilon 4 in Vd, too. A potential protective role of ApoE epsilon 2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.     

Cognitive deficits and polymorphism of apolipoprotein E in Alzheimer's disease

The aim of this study was to test the relationship between apolipoprotein E (ApoE) genotypes and patterns of cognitive deficits in Alzheimer's disease (AD). All subjects were diagnosed as probable AD patients on the basis of the DSM-IV and NINCDS-ADRDA criteria. Each subject was examined for (1) ApoE genotype, (2) general level of mental activity (Global Deterioration Scale and Mini-Mental State Examination) and (3) cognitive functions by means of a battery of neuropsychological tests. On the basis of ApoE genotype, patients were subdivided into two groups: the first group consisted of patients with at least one epsilon4 allele (epsilon4+ group), while the second one consisted of patients without the epsilon4 allele (epsilon4- group). Our results showed that several cognitive processes depended on the ApoE genotype. In early stages of AD, patients from the epsilon4+ group had greater deficits in delayed recall of new information. On the other hand, working memory appeared to be more impaired in the epsilon4- group of patients. Independent of the genotype, both groups showed similar impairment of learning ability without, however, deficits in remote memory.     

Apolipoprotein E epsilon4 allele differentiates the clinical response to donepezil in Alzheimer's disease

The existence of an association between apolipoprotein E (APOE) and Alzheimer's disease (AD) has been reported in several studies. The possession of an ApoE epsilon4 allele is now considered a genetic risk factor for sporadic AD. There has been a growing agreement about the role exerted by the ApoE epsilon4 allele on the neuropsychological profile and the rate of cognitive decline in AD patients. However, a more controversial issue remains about a possible influence of the APOE genotype on acetylcholinesterase inhibitor therapy response in AD patients. In order to address this issue, 81 patients diagnosed as having probable AD were evaluated by a complete neuropsychological test battery at the time of diagnosis (baseline) and after 12-16 months (retest). Patients were divided into two subgroups: (1) treated with donepezil at a dose of 5 mg once a day (n = 41) and (2) untreated (n = 40). Donepezil therapy was started after baseline evaluation. The APOE genotype was determined according to standardized procedures. We evaluated the possible effect of the APOE genotype on the neuropsychological tasks in relation to donepezil therapy. The statistical analysis of the results showed a global worsening of cognitive performances for all AD patients at the retest. Differences in the clinical outcome were analysed in the four subgroups of AD patients for each neuropsychological task. ApoE epsilon4 carriers/treated patients had improved or unchanged scores at retest evaluation for the following tasks: visual and verbal memory, visual attention and inductive reasoning and Mini Mental State Examination. These results indicate an effect of donepezil on specific cognitive domains (attention and memory) in the ApoE epsilon4 carriers with AD. This might suggest an early identification of AD patients carrying at least one epsilon4 allele as responders to donepezil therapy.     

Association between apolipoprotein E genotype and Alzheimer disease in African American subjects

BACKGROUND: The association between Alzheimer disease (AD) and genotypes at the apolipoprotein E (APOE) locus has been confirmed in numerous populations worldwide, but appears to be inconsistent in African American subjects. OBJECTIVE: To investigate the association between APOE genotypes and AD in elderly African American subjects. DESIGN: Clinic-based, multicenter case-control study and a family study. PARTICIPANTS: A total of 338 African American probands meeting criteria for probable or definite AD, 301 cognitively healthy, elderly unrelated control subjects (spouses and community volunteers), and 108 siblings of 88 AD probands. MAIN OUTCOME MEASURES: Odds of AD according to APOE genotype. RESULTS: Compared with individuals with the APOEepsilon3/epsilon3, the odds of having AD were significantly increased among those with 1 or more copies of the epsilon4 allele; the odds ratio (OR) for the epsilon3/epsilon4 genotype was 2.6 (95% confidence interval [CI], 1.8-3.7), and the OR for the epsilon4/epsilon4 genotype was 10.5 (95% CI, 5.1-21.8). These risks decreased substantially after 68 years of age. The risk for AD was lower among individuals with the epsilon2/epsilon3 genotype (OR, 0.41; 95% CI, 0.22-0.79). The patterns of association were similar in men and women. These results obtained from comparisons of unrelated AD patients and controls were bolstered by results of analysis of family data that showed preferential transmission of the epsilon4 allele to demented siblings (P<.001) and of the epsilon2 allele to nondemented siblings (P=.005). CONCLUSIONS: The presence of 1 or 2 epsilon4 alleles is a determinant of AD risk in African American subjects. The age-related risk for decline associated with the epsilon4 allele and the apparent protective effect of the epsilon2 allele are similar to patterns observed in white subjects.     

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.     

Association between apolipoprotein CI HpaI polymorphism and sporadic Alzheimer's disease in Chinese

OBJECTIVE: To investigate into the relationship of apolipoprotein CI (ApoCI) polymorphism with sporadic Alzheimer's disease (AD) in Chinese. SUBJECTS AND METHODS: A total of 257 AD patients and 242 age-matched elderly individuals were genotyped for the ApoCI HpaI and apolipoprotein E (ApoE) HhaI polymorphisms. RESULTS: The ApoCI A allele was associated with AD of moderate to severe dementia when patients were divided into two subgroups according to Clinical Dementia Rating scale, and the AA genotype was strongly associated with moderate to severe AD in ApoE epsilon4 allele carriers [odds ratio (OR) = 8.19, 95% confidential interval: 1.28-52.30, after adjusting for age and gender by logistic regression analysis], although in total no significant differences of allele or genotype frequency between patients and controls were found. CONCLUSION: The present study partially confirmed the previous findings, suggesting that the ApoCI A allele might contribute to the susceptibility to moderate to severe sporadic AD in Chinese.     

Patterns of cognitive impairment and apolipoprotein genotype in persons with Alzheimer's disease

The aim of this study was to test the possible relationship between patterns of cognitive deficits--especially impairment of memory processes--and ApoE genotype in patients with AD. Fifty seven right-handed subjects (31 males and 26 females) were tested in this study. The age of subjects ranged from 50 to 79, the education lasted from 11 to 16 years. All subjects were diagnosed as probable AD patients on the basis of DSM IV and NINCDS-ADRDA criteria. Each subject was examined for: 1) ApoE genotype, 2) general level of activity (GDS and MMSE), 3) neuropsychological evaluation of cognitive processes, using full test battery. 37 patients had at least one of ApoE epsilon 4 allele (e2/4, 3 and 4/4) and 20 patients had none of ApoE 4 allele (e 2/3 and 3/3). The group of tested subjects were subdivided into 2 groups. The first group was comprised by 31 patients with 3-rd stage (according to GDS) of mental activity. Twenty six patients with 4-th stage were included into the second group. Those subgroups did not significantly differ if age, education, gender or ApoE allele were considered. Experimental data were normalized and then analyzed using a statistical package SPSS/PC+. The analysis of variance showed that the type of test, stage of disease and two-way interaction ApoE x type of test were highly significant (P < 0.0001). Some results were obvious and not surprising (e.g. that results of patients with 4-th stage were much worse than the results of patients with stage 3-rd). It turned out that the best results were obtained by our patients in naming tests, the worst--in learning test with distraction. Patients with ApoE epsilon 4 performed better than patients with none ApoE epsilon 4 in the Rey's test, in the similarity test and in the test which required repeating numbers starting from the last one. The differences between the subgroups of patients with different ApoE alleles were confirmed by different distributions of correlations. All statistical analyses were repeated for more homogenous group of patients (only with stage 3-rd). The pattern of results resembled the previous one (i.e. better performance in the same tests) with one exception: additionally, in delayed recall test patients with none ApoE epsilon 4 performed much better that ApoE epsilon 4. Our results showed that some cognitive processes depended on ApoE genotype. Patients with none ApoE epsilon 4 genotype had less severe deficits in delayed recall of new information. On the other hand, working memory appeared to be less affected in patients with ApoE epsilon 4 genotype. Independent of genotype, both group showed similar impairment of learning ability without deficits in remote memory.     

The allele interaction between apolipoprotein epsilon2 and epsilon4 in Taiwanese Alzheimer's disease patients

OBJECTIVE: This study aimed to determine the impact of the present of apolipoprotein epsilon (Apoepsilon) 2 on the relationship between Apoepsilon4 and Alzheimer's disease (AD). METHOD: We examined ApoE genotypes in 428 Taiwanese patients with AD and 807 controls; all participants were older than 65 years. RESULTS: The allele frequency of Apoepsilon4 was greater in AD patients than controls, but significantly lower than in Caucasians. The presence of an epsilon2 allele alone was not associated with lower risk for AD, but the presence of an epsilon2 allele was associated with an epsilon4 allele frequency similar to that of controls. CONCLUSION: The low allele frequency of epsilon4 in persons with an epsilon2 allele suggests that this may be part of the protective effect of epsilon2 against AD.     

Apolipoprotein E polymorphism and age of onset for Alzheimer's disease in a bi-ethnic sample

OBJECTIVE: This study examined the association between the Apolipoprotein-E epsilon4 allele (APOE epsilon4) and age of disease onset in a bi-ethnic sample of community dwelling Alzheimer's disease (AD) patients. DESIGN: Cross-sectional study of AD patients evaluated at a University-affiliated outpatient memory disorders clinic. SUBJECTS: A clinic-based cohort of white non-Hispanic (WNH; n=601) and white Hispanic (WH; n = 359) patients diagnosed with possible or probable AD according to NINCDS-ADRDA diagnostic criteria. MEASURES: Global cognitive functioning of the subjects was evaluated using the Mini-mental State Exam. The age of onset of AD was calculated from the patient's current age minus the reported duration of disease obtained from a knowledgeable family member. RESULTS: A significant relationship was discovered between APOE epsilon4 and age of onset for WNH, with lower ages of onset among patients carrying the epsilon4/epsilon4 and epsilon3/epsilon4 genotypes in relation to patients with the epsilon3/epsilon3 genotype. The results revealed a more modest effect for APOE genotype in the WH cohort, with a lower age of onset witnessed among epsilon4 positive patients (epsilon2/epsilon4, epsilon3/epsilon4 and epsilon4/epsilon4 genotypes) in comparison to epsilon4 negative patients (epsilon2/epsilon2, epsilon2/epsilon3 and epsilon3/epsilon3 genotypes). CONCLUSION: The association between the epsilon4 allele and earlier age of onset was more pronounced in WNH compared to WH patients, suggesting the impact of APOE polymorphism on clinical phenotype may be different for distinct ethnic groups in the U.S.     

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.     

Presenilin gene predisposes to late-onset degenerative but not vascular dementia: a comparative study of PS1 and ApoE genes in a North Indian Cohort

BACKGROUND: Variation in the presenilin gene shifts the cleavage site of amyloid precursor protein producing an insoluble peptide Abeta(42) (instead of Abeta(40), which is soluble when produced in restricted amount), which is prone to aggregation in the brain in the form of amyloid plaques not only in Alzheimer's disease (AD) but also in other degenerative dementias. The role of presenilin 1 (PS1) and apolipoprotein E (ApoE) genes has not been explored in degenerative dementias other than AD. OBJECTIVE: To study the association of PS1 intron 8 and ApoE epsilon4 gene polymorphism in degenerative and vascular dementia patients in the North Indian population. DESIGN: A hospital-based association study on degenerative and vascular dementia patients proven on the basis of clinical profile and MRI. Participants: A group of 107 dementia patients and 162 age- and sex-matched controls from a North Indian cohort participated in the study. All patients had Mini Mental State Examination scores less than 24 and met the DSM-IV criteria for dementia. RESULTS: The frequency of genotype 1/1 and allele 1 in degenerative dementias (73.12 and 83.70%, respectively) was higher than what had been reported so far in AD. A significant association of PS1 intron 8 polymorphism was found with degenerative dementias but not with vascular dementias (OR 2.50, 95% CI 1.27-5.00). On the other hand, ApoE epsilon4 allele was found to significantly increase the risk for both vascular and degenerative dementias (p = 0.0001, OR 3.45, 95% CI 1.74-6.86). CONCLUSION: While ApoE epsilon4 allele increases the susceptibility to both degenerative and vascular dementia, PS1 allele 1 increases the susceptibility to degenerative dementias only.     

Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer's disease

A variety of anatomic and functional neuroimaging findings are associated with Alzheimer's disease (AD). One of the strongest imaging associations identified is between AD and hippocampal atrophy. The ∈4 allele of the apolipoprotein E (ApoE) gene increases the risk of developing AD and lowers the mean age of onset of the disease. The purpose of this study was to assess the association between hippocampal volume and ApoE polymorphisms in elderly control subjects and in patients with probable AD. We performed magnetic resonance imaging–based volume measurements of the hippocampus in 125 cognitively normal elderly controls and 62 patients with probable AD. ApoE genotyping was performed by using standard methods. Hippocampal volumes were significantly smaller in AD cases than in control subjects. Hippocampal volumes did not differ significantly within either clinical group on the basis of ApoE genotype. Both the ∈4 allele of ApoE and hippocampal atrophy were significantly but independently associated with AD.     

Apolipoprotein-E (APO-E) genotype and symptoms of psychosis in Alzheimer's disease.

The authors examined the association of Apolipoprotein-E (APO-E) genotype to symptoms of psychosis and depression in 501 patients diagnosed with probable (n=343) or possible (n=158) Alzheimer's disease (AD) according to NINCDS-ADRDA criteria. They observed the following APO-E genotypes: epsilon2/epsilon3 (n=19); epsilon2/epsilon4 (n=14); epsilon3/epsilon3 (n=228); epsilon3/epsilon4 (n=203); epsilon4/epsilon4 (n=37). In contrast to previous reports, the results did not indicate a relationship between either the epsilon4 allele or the epsilon2 allele and symptoms of mood disturbance in AD. However, an elevated risk for psychosis was shown, specifically, at the severe stage of cognitive impairment, among AD patients carrying the epsilon4 allele, after effects of age, gender, education, and level of cognitive impairment were controlled.     

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.     

Apolipoprotein E epsilon4 allele frequency in vascular dementia

AIM: The aim of the study was to investigate whether possession of the epsilon4 allelic form of the apolipoprotein E (APOE) gene increases the risk of developing vascular dementia (VaD). METHODS: APOE allele and genotype frequencies were determined by PCR in 89 patients with possible and probable VaD and compared with those in 97 patients with possible and probable Alzheimer's disease (AD) of similar age of disease onset and ethnic background, and with 766 control subjects drawn from the same geographical region. RESULTS: The APOE epsilon4 allele frequency in all 97 patients with possible and probable AD was significantly higher (p < 0.001) than that in control subjects. However, the APOE epsilon4 allele frequency in all 89 patients with possible and probable VaD was also significantly higher (p < 0.001) than that in control subjects, but not significantly different from that in AD. The APOE epsilon4 allele frequency was similarly, and still significantly (p < 0.001), increased when only those patients with probable AD or probable VaD were considered. CONCLUSION: Possession of APOE epsilon4 allele increases the risk of VaD.     

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.