APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis.

OBJECTIVE: To determine whether a specific apolipoprotein E (APOE) polymorphism is a risk factor for ischemic cerebrovascular disease (CVD; stroke or TIA). BACKGROUND: The APOE epsilon4 allele is overrepresented in AD, atherosclerosis, and ischemic heart disease. In addition, epsilon4 carriers have higher plasma cholesterol levels than non-epsilon4 carriers. METHODS: Using Medline (OVID and PubMed), a search was performed for all studies that examined APOE in ischemic CVD. The authors identified nine case-control studies that were suitable for analysis. RESULTS: There were 926 patients with ischemic stroke or TIAs and 890 age- and sex-matched control subjects. Overall analysis revealed a significantly higher APOE-epsilon4 allelic frequency in affected patients compared with control subjects (0.14 versus 0.09; odds ratio, 1.68; 95% CI, 1.36 to 2.09; p<0.001). There was a significant excess of the epsilon3 allele (0.85 versus 0.80) but not the epsilon2 allele (0.06 versus 0.06) in the control subjects compared with the ischemic CVD patients. Seven studies had data on APOE genotypes. Carriers of epsilon4 were more frequent among ischemic CVD patients than control subjects (27% versus 18%; odds ratio, 1.73; 95% CI, 1.34 to 2.23; p<0.001). CONCLUSIONS: The APOE-epsilon4 allele and carriers of epsilon4 are more frequent among patients with ischemic CVD compared with control subjects. The epsilon2 allele does not appear to be protective for ischemic CVD. These findings imply a role for the APOE genotype in the pathogenesis of some cases of ischemic CVD.     

Premorbid cognitive testing predicts the onset of dementia and Alzheimer's disease better than and independently of APOE genotype

OBJECTIVE: To determine whether a cognitive test package can predict the onset of dementia up to 11 years later, and the extent to which this prediction is independent of that provided by APOE genotype. METHODS: Prospective cohort study based on 54 general practices in the UK; 657 survivors of the 1088 participants in the MRC treatment trial of hypertension in older adults were followed for up to 11 years; 370 participants (57% of survivors) were traced, screened for dementia, and genotyped for APOE in 1994. Baseline assessments included trail making test A, paired associated learning test, Raven's progressive matrices, and national adult reading test. At follow up, both mini-mental state examination and CAMCOG were used. Outcome measures were DSM-IIIR dementia and NINCDS-ADRDA possible and probable Alzheimer's disease. RESULTS: All the cognitive tests completed in 1983 predicted onset of dementia and Alzheimer's disease up to 11 years later, as did APOE genotype. Cognitive test performance was not associated with APOE genotype. Addition of cognitive tests increased the area under the ROC curve for the prediction of Alzheimer's disease provided by age, family history, and APOE genotype (0.81 v 0.69, p = 0.048); addition of APOE genotype did not increase the area under the ROC curve for the prediction provided by age, family history, and cognitive tests (0.81 v 0.77, p = 0.28). CONCLUSIONS: Simple tests of cognitive ability provide useful predictive information up to a decade before the onset of dementia. The predictive information provided is independent of, but not enhanced by, the addition of APOE genotype.     

APOE-epsilon4 predicts dementia but not other psychiatric disorders after traumatic brain injury

The authors studied the association between APOE-epsilon4 genotype and axis I and II psychiatric disorders an average of 30 years after traumatic brain injury. Sixty patients were dichotomized into subjects with and without APOE-epsilon4 allele. Dementia and subclinical dementia were significantly more common with the presence of APOE-epsilon4. The occurrence of other psychiatric disorders did not differ between patients with and without APOE-epsilon4 allele.     

Association between platelet glycoprotein Ibalpha genotype and ischemic cerebrovascular disease

BACKGROUND AND PURPOSE: Platelets play pivotal roles in the development of ischemic cerebrovascular disease (CVD). The platelet glycoprotein (GP) Ib/IX/V complex is a receptor for von Willebrand factor, which plays a major role in the initial phase of platelet activation under high shear stress conditions. This study was designed to investigate the association between a genetic variation of this receptor and the prevalence of CVD. METHODS: Two hundred patients with ischemic CVD, as confirmed by brain CT and/or MRI, and 317 age- and sex-matched control subjects without clinical evidence of CVD or cardiovascular disease were analyzed for their genotype frequencies of the (145)Thr/Met dimorphism of the alpha-chain of GPIb (GPIbalpha). RESULTS: Genotypes with (145)Met (T/M and M/M) were more frequently found in the CVD patients (26.5%) than in control subjects (14.2%, P=0.0005). The genotype effect was more obvious in those <60 years of age or without acquired cardiovascular risk factors. The odds ratio for nonsmoking women <60 years of age was 10. 6 (95% confidence intervals, 2.2 to 51.7). Although the number of patients studied was small (n=24), transient ischemic attack showed the highest odds ratio (4.3, P=0.0004), followed by lacunar infarction (OR=2.2, P=0.0024) and atherothrombotic infarction (OR=1. 5, P=0.3143). Logistic regression analysis revealed that the presence of Met-allele was independently associated with CVD. CONCLUSIONS: Our study suggests that the platelet GPIbalpha genotype is a genetic risk factor for ischemic CVD.     

Metrifonate treatment of AD: influence of APOE genotype

OBJECTIVE: To investigate whether an interaction exists between APOE genotype and the response of AD patients to metrifonate treatment and whether APOE genotype independently affects the rate of AD progression. BACKGROUND: Metrifonate is a new acetylcholinesterase inhibitor for the treatment of AD symptoms. METHODS: Data were pooled from four prospective, randomized, double-blind, placebo-controlled clinical trials and analyzed retrospectively. A total of 959 patients who received once-daily placebo (n = 374) or metrifonate (30 to 60 mg based on weight or a 50-mg fixed dose, n = 585) for up to 26 weeks agreed to APOE genotyping. RESULTS: Metrifonate clearly improved the cognitive performance of the AD patients when compared with placebo (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], p = 0.0001). The interaction of APOE genotype and the metrifonate effect on cognitive performance were not significant (p = 0.25). Metrifonate also clearly improved the global function of the AD patients when compared with placebo (Clinician's Interview-Based Impression of Change with Caregiver Input [CIBIC-Plus], p = 0.0001). The interaction of APOE genotype with the metrifonate effect on global function also was not significant (p = 0.70). No significant three-way interactions were observed among APOE genotype, gender, and response to metrifonate treatment (ADAS-Cog, p = 0.68; CIBIC-Plus, p = 0.26). APOE genotype did not influence disease progression as evaluated by either cognitive performance (ADAS-Cog, p = 0.93) or global function (CIBIC-Plus, p = 0.64). CONCLUSIONS: The findings from these studies of up to 26 weeks' duration do not clearly support an interaction between APOE genotype and metrifonate treatment effects. They suggest that APOE genotypes do not necessarily predict an AD patient's response to metrifonate treatment and that APOE genotype may not influence the rate of disease progression for patients with mild to moderate AD.     

APOE genotype predicts depression in women with Alzheimer's disease: a retrospective study

OBJECTIVE: The association between the APOE epsilon4 allele and depression was investigated in a retrospective study of 323 AD patients. METHODS: Patients were divided into demographically comparable groups based on the presence or absence of depression. RESULTS: Results showed that the frequency of APOE epsilon4 allele was significantly higher in the depressed vs non-depressed AD patients (72% and 58%, respectively), and an interaction revealed that women possessing the APOE epsilon4 allele were almost four times more likely to be depressed than those without the epsilon4 allele. CONCLUSION: Results are consistent with recent suggestions that the APOE epsilon4 genotype may be over-represented among depressed women with AD and highlight the need for additional research investigating the links between APOE genotype, mood, and gender.     

Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease

OBJECTIVE: To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI). BACKGROUND: Previous cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI. METHODS: Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability. RESULTS: Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline. CONCLUSIONS: Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.     

Confabulation, but not executive dysfunction discriminate AD from frontotemporal dementia

We examined confabulation and performance on frontal/executive tasks in Alzheimer's disease (AD) patients and patients with a diagnosis of probable frontotemporal dementia (FTD). Twenty-two patients with probable AD, 10 patients with probable FTD and 32 normal control subjects entered the study. Executive functions were assessed with the Modified Card Sorting test; a verbal fluency test; the Cognitive Estimation test; and the Stroop test. Confabulations were assessed with a modified version of the Confabulation Battery. The Confabulation Battery included 10 questions tapping each of the following domains: Episodic Memory (memories of personal past episodes), Semantic Memory (knowledge of famous facts and famous people), and Personal Future (personal plans). The results revealed that both AD patients and FTD patients were clearly and equally impaired on tests of executive functions. Both patients' groups confabulated across the three tasks of the Confabulation Battery, but FTD patients confabulated significantly more than AD patients on Episodic Memory and Personal Future. The results failed to provide any evidence of a correlation between the performance on frontal/executive tasks and the tendency to produce confabulatory reports. According to our results, confabulation, more than a deficit of frontal/executive functions, discriminate between AD and FTD. Therefore, screening for confabulation and, possibly, for other types of memory distortions may constitute a useful additional clinical tool in order to discriminate AD from FTD.     

Increased CSF cortisol in AD is a function of APOE genotype

BACKGROUND: Increased hypothalamic-pituitary-adrenal (HPA) axis activity manifested by elevated cortisol levels is observed in AD and may contribute to AD by lowering the threshold for neuronal degeneration. Presence of the APOE-epsilon4 allele increases risk for AD. Increased cortisol concentrations in apoE-deficient mice suggest that APOE genotype may influence cortisol concentrations in AD. METHODS: The authors measured cortisol levels in CSF and determined APOE genotypes for 64 subjects with AD and 34 nondemented older control subjects. RESULTS: CSF cortisol was significantly higher in AD than in control subjects. CSF cortisol concentrations differed with respect to APOE genotype in both subjects with AD (epsilon4/epsilon4 > epsilon3/4epsilon > epsilon3/epsilon3) and normal older control subjects (epsilon3/epsilon4 > epsilon3/epsilon3 > epsilon2/epsilon3). Comparison of CSF cortisol concentrations within the epsilon3/epsilon4 and epsilon3/epsilon3 genotypes revealed no differences between AD and control subject groups. CONCLUSIONS: Higher CSF cortisol concentrations were associated with increased frequency of the APOE-epsilon4 allele and decreased frequency of the APOE-epsilon2 allele in AD subjects relative to control subjects. This effect of APOE genotype on HPA axis activity may be related to the increased risk for AD in persons carrying the APOE-epsilon4 allele and decreased risk for AD in persons carrying the APOE-epsilon2 allele.     

Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD

OBJECTIVE: To compare regional cerebral blood flow (rCBF) changes using 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT in subjects with dementia with Lewy bodies (DLB) and AD and in normal age-matched control subjects; to examine the utility of SPECT changes in the differential diagnosis of AD and DLB. METHOD: Whole-brain SPECT scans were acquired using a single-headed rotating gamma camera (IGE CamStar XR/T) in elderly subjects with consensus criteria DLB (n = 23; mean age = 79.4 years), National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association AD (n = 50; 81.9 years), and normal control subjects (n = 20; 78.1 years) after injection with 500 MBq of 99mTc-HMPAO. Region-of-interest analysis was performed using a SPECT template registered in Talairach space, with rCBF normalized to cerebellum. RESULTS: Both DLB and AD subjects had significantly reduced rCBF in parietal and temporal regions compared with the control subjects. The AD group also showed a significant reduction in rCBF in the frontal and medial temporal regions and the DLB in the occipital areas compared with control subjects. AD and DLB groups differed only in occipital perfusion (p < 0.01). SPECT measures (occipital and medial temporal) correctly classified 69% of all subjects, with a 65% sensitivity and 87% specificity for DLB against AD and control subjects. CONCLUSION: Temporoparietal hypoperfusion on SPECT is common to both AD and DLB. Occipital hypoperfusion is more frequently seen in DLB. Although not diagnostically specific in individual cases, occipital hypoperfusion on SPECT should raise suspicion that DLB may be the cause of dementia, prompting careful search for other features of the disorder.     

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.     

血管生成素与缺血性脑血管病

血管生成素（ANG）具有促血管生成作用,本文着重阐述ANG的生理作用及其促血管生成的机制,重点介绍缺血性脑血管病（ICVD）时ANG的表达及其对ICVD的保护及治疗作用。     

APOE genotype and cholesterol levels in lewy body dementia and Alzheimer disease: investigating genotype-phenotype effect on disease risk.

BACKGROUND: APOE is the most recognized genetic risk factor for sporadic late-onset Alzheimer disease (AD). The role of APOE genotype in Lewy body dementia (LBD) is still unknown as well as the relationship between APOE genotype and cholesterol levels. OBJECTIVE: The objective of this study was to explore the association between APOE genotype and cholesterol levels in patients with LBD and those with AD. METHODS: Eighty-two patients with LBD were consecutively enrolled as well as a comparable number of patients with AD and comparison group. Each subject underwent a clinical and neuropsychologic evaluation and APOE genotyping. RESULTS: The distribution of APOE genotypes significantly differed between AD and LBD cases compared with the comparison group, with the APOE epsilon4+ (epsilon4+/epsilon4 + or epsilon4+/epsilon4-) genotype more frequent in patient subgroups. Different models have been fitted, and total APOE epsilon4-hypercholesterolemia complete interaction effect was claimed in predicting their relationship on disease outcome. Subjects with hypercholesterolemia and heterozygous for APOE epsilon4 allele had more than threefold risk to develop AD compared both with the comparison group and with those with LBD. The risk to develop AD in hypercholesterolemic and APOE epsilon4 homozygous subjects was 13-fold compared with the comparison group and those with LBD. Conversely, there was not evidence for APOE epsilon4-hypercholesterolemia complete interaction effect in LBD and in the comparison group. CONCLUSIONS: This study highlighted that APOE is a risk factor not only for AD, but also for LBD, and that the APOE-cholesterol pathway differently affects AD and LBD. This approach may aid the search for the identification of an interactive effect of APOE genotype and modifiable risk factors, i.e., hypercholesterolemia, eventually resulting in individualized and effective cholesterol-lowering therapy in at-risk subjects.     

APOE genotype, plasma lipids, lipoproteins, and AD in community elderly.

BACKGROUND: Genetic variation at the APOE locus has a major influence on both plasma lipid levels and the risk of AD. The relationship between APOE genotype and plasma lipids may influence the risk of AD. OBJECTIVE: In a community-based study of white, African American, and Caribbean Hispanic elderly in New York City, we investigated the relationship between plasma lipids and AD as well as the possible influence of APOE genotype on this relationship. METHODS: Total plasma cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were investigated in a cross-sectional study of nondemented elderly and patients with AD and in a prospective study of incident AD. Analyses included APOE genotype, gender, ethnicity, body mass index, and other potential confounders such as a history of hypertension, smoking, aspirin use, previous stroke, or ischemic heart disease. RESULTS: Compared with nondemented elderly, decreased TC level had a weak but significant inverse association with incident AD, independent of APOE genotype. No other lipoprotein fragment was associated with either prevalent or incident AD. CONCLUSION: Our results suggest that no consistent relationship exists between APOE genotype, plasma lipoproteins, and AD.     

Serum lipoprotein profile and APOE genotype in Alzheimer's disease

Alterations in cholesterol homeostasis are associated with Alzheimer's disease (AD). The role played by specific fractions of serum lipoproteins in modifying the risk of AD, and the interaction with APOE genotype has not yet been investigated. We studied serum lipoprotein profiles using a gradient-density ultracentrifugation method in a cohort of late-onset sporadic AD patients without cerebrovascular lesions and in healthy elderly subjects. In the AD group the lipoprotein cholesterol distribution showed an increase in LDL cholesterol, reaching a significant difference with respect to controls in the LDL sub-fractions representing the transition between small dense-LDL (fraction 11, p = 0.04) and normal-density LDL particles (fraction 12, p = 0.03). APOE genotype and LDL cholesterol were independently associated with AD. The mean concentration of LDL in fractions 11 and 12 increased the risk of developing AD (p = 0.01 and p = 0.025, respectively). These results confirm that an alteration of cholesterol homeostasis is associated with AD and that serum concentrations of LDL cholesterol are higher in AD patients without cerebrovascular pathology than in elderly normal subjects. The presence of the APOE epsilon4+ allele is a risk factor for AD independent of increased serum cholesterol or a modification of other vascular risk factors. Increased levels of specific sub-fractions of LDL cholesterol may be associated with increased risk of AD.