Apo Phenotypes Research Articles

Impact of apolipoprotein(a) phenotypes on long-term renal transplant survival.

The long-term success of renal transplantation is limited because of chronic rejection (CR), which shows histologic parallels to atherosclerosis. Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis, but its role in CR has not been investigated. Plasma levels of Lp(a) are determined mainly by the inherited isoform (phenotype) of apolipoprotein(a) [apo(a)] and show an inverse correlation with the molecular weight of apo(a). Apo(a) isoforms were identified in frozen sera of 327 patients who received a renal transplant during 1982 to 1992. Long-term graft survival in recipients with high molecular weight (HMW) or low molecular weight (LMW) apo(a) phenotypes were compared retrospectively. Mean (95% confidence interval) transplant survival was 12.8 yr (range, 11.9 to 13.6 yr) in patients with HMW and 11.9 yr (range, 10.8 to 13.1 yr) in patients with LMW apo(a) phenotypes (P = 0.2065). In patients who were 35 yr or younger at the time of transplantation, mean transplant survival was more than 3 yr longer in recipients with HMW apo(a) phenotypes compared with those with LMW apo(a) phenotypes (13.2 yr [range, 12.1 to 14.4 yr] versus 9.9 yr (range, 8.5 to 11.5 yr); P = 0.0156). In a Cox's proportional hazards regression model, the presence of LMW phenotypes-but not gender, immunosuppression, or HLA mismatches-in young patients was associated with a statistically significant risk of CR (P = 0.0434). These retrospective data indicate that young renal transplant recipients with LMW apo(a) phenotypes have a significantly shorter long-term graft survival, regardless of the number of HLA mismatches, gender, or immunosuppressive treatment.

Gene correction of apolipoprotein (APO) E2 and APOE4 phenotypes to wild-type APOE3 by in situ chimeraplasty

Gene correction of apolipoprotein (APO) E2 and APOE4 phenotypes to wild-type APOE3 by in situ chimeraplasty

Apolipoprotein-E phenotype and basal activity of low-density lipoprotein receptor are independent of changes in plasma lipoprotein subfractions after cholesterol ingestion in japanese subjects

We investigated whether the apolipoprotein-E (apoE) phenotype and the basal activity of low-density lipoprotein (LDL) receptor, which were reported to be the major determinants for increase in plasma LDL levels by cholesterol ingestion, have the same role in Japanese subjects whose diet is low in fat and cholesterol. Cholesterol (750 mg/d) was added to the ordinary diet as a dried egg-yolk supplement for 4 wk to 110 subjects. Plasma levels of lipids, apolipoproteins, and cholesterol in lipoprotein subfractions were measured at the beginning and end of the test period. Phenotyping of apoE was determined by an isoelectric focusing-immunoblotting method, and LDL receptor activity in lymphocytes was determined by flow cytometry. Plasma levels of cholesterol in less-dense LDL (LDL 1) and less-dense high-density lipoprotein (HDL 2) were slightly but significantly increased, 3.4% and 4.1%, respectively, by cholesterol ingestion, but the increases were not statistically significant in any of E2, E3, and E4 groups. The distribution of the apoE phenotype was equivalent in all three LDL-cholesterol groups (no change, increase, and decrease by cholesterol ingestion). Plasma levels of LDL, LDL 1, and LDL 2 cholesterol were not significantly increased in the three groups of subjects with lymphocyte LDL-receptor activities (low, medium, and high). As with apoE phenotype, LDL-receptor activities were the same in all three LDL-cholesterol groups. In addition, there were no significant correlations between LDL-receptor activity and changes in plasma levels of lipids, apolipoproteins, and cholesterol in lipoprotein subfractions. Therefore, we concluded that cholesterol ingestion significantly increases plasma levels of less-dense LDL and HDL, but neither apoE phenotype nor basal LDL-receptor activity explain the variability in changes in plasma lipoprotein subfractions by cholesterol ingestion in Japanese subjects.

Gene Correction of the Apolipoprotein (Apo) E2 Phenotype to Wild-type ApoE3 by in Situ Chimeraplasty

Apolipoprotein (apo) E is a polymorphic plasma protein, synthesized mainly by liver. Here, we evaluate whether synthetic DNA-RNA oligonucleotides (chimeraplasts) can convert a dysfunctional isoform, apoE2 (C --> T, R158C), which causes Type III hyperlipidemia and premature atherosclerosis, into apoE3. First, we treated recombinant Chinese hamster ovary cells stably secreting apoE2 with a 68-mer apoE2 to apoE3 chimeraplast. About one-third of apoE2 was converted to apoE3, and the repair was stable through 12 passages. Subcloning treated cells produced both apoE2 and apoE3 clones. Direct sequencing and reverse transcription polymerase chain reaction confirmed the genotype, whereas phenotypic change was verified by isoelectric focusing and immunoblotting of secreted proteins. Second, we established that the APOE2 gene can be targeted both in vivo, using transgenic mice overexpressing human apoE2, and in chromosomal context, using cultured lymphocytes from a patient homozygous for the epsilon2 allele. We conclude that chimeraplasty has the potential to convert the apoE2 mutation in patients with Type III hyperlipidemia to apoE3.

APOE-epsilon4 is associated with weight loss in women with AD: a population-based study.

To investigate whether the APOE-epsilon4 allele is associated with weight loss in patients with AD or in nondemented elderly subjects. Weight loss has been considered a typical feature of AD. APOE-epsilon4 is a risk factor for AD and was recently proposed to be associated with weight loss in elderly women. It is not known whether APOE-epsilon4 is associated with weight loss in patients with AD or in the general population. Weight and BMI measurements at an average interval of 3.5 years and APOE phenotype determination were performed in an elderly population (n = 980), including 46 patients with AD and 911 control subjects at the end of the follow-up. On average, patients with AD with the epsilon4 allele lost 1.9 +/- 4.0 kg (BMI 0.8 +/- 1.8 kg/m2) whereas epsilon4 noncarriers gained 1.2 +/- 3.8 kg (BMI 0.4 +/- 1.5 kg/m2) (both p < 0.05), after controlling for diabetes and exercise. However, when men and women were analyzed separately, weight loss was observed only in those women with AD with the epsilon4 allele. Clinically significant weight loss, defined as loss of > or = 5% of body weight, occurred more frequently in both patients with AD (30% versus 6%; p < 0.05) and control subjects (28% versus 18%; p < 0.001) carrying the epsilon4 allele. The APOE-epsilon4 allele may contribute to the unexplained weight loss in AD, especially in women.

A new DNA polymorphism in the 5′ untranslated region of the human SREBP-1a is related to development of atherosclerosis in high cardiovascular risk population

Sterol-regulatory element binding proteins (SREBPs) are ubiquitous transcription factors that regulate the genes encoding key proteins in the control of cholesterol homeostasis. We looked for mutations or polymorphisms within the sequences of the SREBP-1a gene critical for the synthesis and/or activity of the protein in 204 asymptomatic men. A single G deletion at base pair −36 of the translation initiation site (designated G-) was found using single-strand conformation polymorphism (SSCP), in addition to three rare variants. This new marker was then assessed for its influence on the lipid parameters of 812 men at high cardiovascular risk, and on the presence of echographic atherosclerotic plaque in their peripheral arteries. The allelic frequency of the −36delG polymorphism was 0.58. At least one plaque was found in the carotid in 24% of subjects, in the femoral arteries of 48%, and in the aorta of 25%. There were significant associations between the −36delG polymorphism and mean total cholesterol ( p=0.02) and LDL-cholesterol ( P=0.02). There was a graded relationship between the G- allele and the presence of carotid plaque ( r=0.084, P=0.02). In addition, there was a statistically significant interaction between the −36delG genotype and the apoE phenotype for plasma LDL-cholesterol ( P=0.04) and apoB ( P=0.05), suggesting a gene–gene interaction. Stepwise multiple regression analysis for lipid traits, risk factors, and apoE phenotype showed an independent association between carotid plaque and the −36delG polymorphism ( β=0.311, P=0.03). Thus, we have identified a new polymorphism in the 5′ untranslated region of the SREBP-1a gene, and demonstrated its association with an atherogenic lipid profile and echographic plaques.

Apolipoprotein E phenotype and the efficacy of intravenous tissue plasminogen activator in acute ischemic stroke.

We used stored plasma samples from 409 patients in the National Institute of Neurological Diseases and Stroke (NINDS) tissue plasminogen activator (t-PA) Stroke Trial to examine the relationship between an apolipoprotein (Apo) E2 or an Apo E4 phenotype and a favorable outcome 3 months after stroke, the risk of intracerebral hemorrhage, and the response to intravenous t-PA therapy. For the 27 patients with an Apo E2 phenotype who were treated with t-PA, the odds ratio (OR) of a favorable outcome at 3 months was 6.4 [95% confidence interval (CI) 2.7-15.3%] compared to the 161 patients without an Apo E2 phenotype who were treated with placebo. The 190 patients treated with t-PA who did not have an Apo E2 phenotype also had a greater, though less pronounced, likelihood of a favorable outcome (OR 2.0, 95% CI 1.2-3.2%) than patients without an Apo E2 phenotype treated with placebo. For the 31 patients with an Apo E2 phenotype treated with placebo, the OR of a favorable 3 month outcome was 0.8 (95% CI 0.4-1.7%) compared to the 161 patients without an Apo E2 phenotype treated with placebo. This interaction between treatment and Apo E2 status persisted after adjustment for baseline variables previously associated with 3 month outcome, for differences in the baseline variables in the two treatment groups and in the Apo E2-positive and -negative groups, and for a previously reported time-to-treatment x treatment interaction (p = 0.03). Apo E4 phenotype, present in 111 (27%) of the 409 patients, was not related to a favorable 3 month outcome, response to t-PA, 3 month mortality, or risk of intracerebral hemorrhage. We conclude that the efficacy of intravenous t-PA in patients with acute ischemic stroke may be enhanced in patients who have an Apo E2 phenotype, whereas the Apo E2 phenotype alone is not associated with a detectable benefit on stroke outcome at 3 months in patients not given t-PA. In contrast to prior studies of head injury and stroke, we could not detect a relationship between Apo E4 phenotype and clinical outcome.

Apolipoprotein E1 Baden (Arg 180→Cys) : A new apolipoprotein E variant associated with hypertriglyceridemia

Apolipoprotein (apo) E mediates the removal of chylomicron and very low density lipoprotein remnants from plasma. It is polymorphic in sequence and the products of the three common alleles ( ϵ2, ϵ3, ϵ4) differ from one another in their binding to lipoprotein receptors. ApoE2 is defective in binding and homozygosity for apoE2 is associated with type III hyperlipoproteinemia (HLP). Other rare isoforms of apoE have been found to be associated either with dominant type III HLP or with the development of hypertriglyceridemia. We identified a 42 year-old hypertriglyceridemic woman with an apoE phenotype 3/1. Restriction isotyping using AflIII /HaeII resulted in an apparent apoE genotype 3/2, suggesting that the mutation occurred in an ϵ2 allele. DNA sequence analysis revealed a C→T point mutation at the first position of the codon for amino acid residue 180 of the mature apoE. This predicted a change Arg 180→Cys. The mutation altered a recognition site for the endonuclease HaeII, which allowed us rapidly to screen for this mutation. In relatives of the proband, apoE1 Baden was consistently associated with hypertriglyceridemia. Similar to other apoE variants linked to hypertriglyeridemia, the Arg 180→Cys mutation is located within the lipid binding domain of apoE. We therefore suggest that apoE1 Baden may cause hypertrigylceridemia, possibly by inhibiting the hydrolysis of triglycerides associated with very low density lipoproteins.

Relationship of Lipoprotein(a) to Variables of Coagulation in Hypertensive Subjects

BackgroundCoagulation factors are independent predictors of cardiovascular damage in the general population. The purpose of this study was to investigate the relationships between general cardiovascular risk factors, lipoprotein(a) (Lp(a)), and...

Apolipoprotein(a) Phenotype, Albumin Clearance, and Plasma Levels of Lipoprotein(a) in Peritoneal Dialysis

This cross-sectional study was undertaken to examine the relationship between plasma lipoprotein(a) [Lp(a)] level and peritoneal dialysis (PD) albumin clearance while controlling for the influence of the apolipoprotein(a) [apo(a)] phenotype. Plasma Lp(a) level, PD albumin clearance, and apo(a) phenotype (high vs. low molecular weight, HMW vs. LMW) were determined in 54 PD patients. Apo(a) phenotypes were 24 LMW and 30 HMW. The plasma Lp(a) level was high (>65 nmol/l) in 17 of 24 patients with LMW phenotype versus 2 of 30 with HMW phenotype (χ², p < 0.01). Spearman correlation coefficients of Lp(a) with PD, urine, and total albumin clearances were –0.05 (p = 0.74), –0.04 (p = 0.80), and –0.09 (p = 0.51), respectively. The apo(a) isoform size was the only significant predictor of Lp(a) in multivariate analysis. In this study, there was no association between PD albumin clearance and Lp(a) level. The association between apo(a) phenotype and Lp(a) level is in keeping with studies in the general population. There is a strong genetic influence on Lp(a) level in PD patients.

Apolipoprotein E phenotypes in rheumatoid arthritis with or without amyloidosis

The role of apolipoprotein (apo) E in the pathogenesis of reactive amyloidosis is unclear. Here we evaluated the apoE phenotype distribution and apolipoprotein e allele frequencies in 55 adult patients with seropositive, erosive RA with amyloid and compared them with 55 matched RA patients without amyloid. The apoE isotypes were determined by isoelectric focusing and immunoblotting. RA patients without amyloid had more often the apoE 3/3 phenotype (71%) than the RA+A patients (49%, P<0.05) or Finnish control subjects (47%, P<0.01) and the frequency of the apoe3 allele was significantly higher among the RA patients without amyloid than among RA+A patients (P<0.05) or control subjects (P<0.01). The prevalence of the apoE3/4 phenotype among the RA+A patients, although higher, did not significantly differ from the RA patients without amyloid (40% and 26%, respectively, NS) or Finnish control subjects (40% and 35%, respectively, NS). The frequency of the apoe4 allele among the RA+A patients did not signficantly differ from that of RA patients without amyloid (0.23 and 0.13, respectively, NS) or Finnish control subjects (both 0.23). However, the apos4 frequency of 0.13 among the RA patients without amyloid was significantly lower than that of Finnish control subjects (0.23, P<0.05). We conclude that the prevalence of the apoE4 isotype is not increased in patients with RA complicated by amyloidosis when compared with Finnish control subjects. Since the frequency of the apoe4 allele is significantly decreased in RA patients without amyloid when compared with Finnish control subjects, the presence of the apoE4 in a patient with RA could, though, represent a relative risk factor for developing reactive amyloidosis.

Relationship between oxidative stress and apoE phenotype in Alzheimer's disease.

To investigate the relationship between oxidative stress and apoE phenotype in dementia of Alzheimer type (DAT). Hydroxyl radical content in blood, superoxide dismutase (SOD) activity in red blood cells (RBC) and plasma, Cu,Zn-SOD protein content in RBC, and apoE phenotype were determined in 24 DAT patients and 25 controls. DAT patients with the apoE4 phenotype showed higher hydroxyl radical levels than DAT patients without the apoE4 phenotype or controls. SOD activities and Cu,Zn-SOD protein levels in RBC of DAT patients with and without the apoE4 phenotype showed no significant differences, but values in both patient groups were lower than in controls. The apoE4 phenotype was more prevalent in DAT patients than in controls. DAT patients with the apoE4 phenotype were younger at disease onset than DAT patients without the apoE4 phenotype. Our findings suggest that apoE4 and SOD individually influence oxidative stress in DAT.

Differences in HDL-cholesterol:apoA-I + apoA-II ratio and apoE phenotype with albuminuric status in Type I diabetic patients.

To examine whether the HDL-cholesterol:apoA-I + apoA-II ratio and the epsilon2 allele are related to albuminuria at baseline and whether they are risk factors for progression of albuminuria in a cohort study of patients with Type I (insulin-dependent) diabetes mellitus. At baseline, the study cohort comprised 617 patients, aged 15-60 years, from seven European diabetic centres of the EURODIAB study. Albumin excretion rate, measured in a central laboratory, was categorised as normoalbuminuria at 20 microg/min or less, microalbuminuria between 20 and 200 microg/min or macroalbuminuria at 200 microg/min or over. Of the 250 patients who were normoalbuminuric at baseline and had follow-up albuminuria measurements, 34 patients were defined as early progressors. At baseline, the mean HDL-cholesterol:apoA-I + apoA-II ratio was lower in macroalbuminuric patients (0.79, 95 % CI:0.74-0.83) compared with normoalbuminuric (0.88, 95 % CI:0.87-0.90) patients (p = 0.0002, adjusted for age and sex). At follow-up, 34 patients who progressed from normoalbuminuria to microalbuminuria or macroalbuminuria also had a slightly lower baseline ratio (0.85, 95% CI:0.80-0.89) than those 216 who remained normoalbuminuric (0.89, 95 % CI:0.87-0.92) (adjusted p = 0.08). Neither of these relations were independent of LDL-cholesterol or fasting triglyceride. There was no association of the epsilon2 allele with albuminuria either at baseline (OR = 1.4, 95% CI:0.7-2.8) or with progression of albuminuria (OR = 0.4, 95 % CI:0.1-3.5). There is an inverse relation of HDL-cholesterol:apoA-I + apoA-II ratio with albuminuria at baseline. This lower ratio in microalbuminuric or macroalbuminuric patients could contribute to the increased risk of cardiovascular disease associated with nephropathy. There is weak evidence that HDL-composition is a risk factor for progression of albuminuria and no association of the epsilon2 allele with diabetic nephropathy.

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.

Genotypes and Phenotypes for Apolipoprotein E and Alzheimer Disease in the Honolulu-Asia Aging Study

The utility of apolipoprotein E (ApoE) type as an indicator of genetic susceptibility to Alzheimer disease (AD) depends on the reliability of typing. Although ApoE protein isoform phenotyping is generally assumed equivalent to genotyping from DNA, phenotype-genotype differences have been reported. ApoE genotype and phenotype results were examined for 3564 older (ages 71-93 years) Japanese-American male participants of the Honolulu-Asia Aging Study, an ongoing population-based study of aging and dementia. Both methods demonstrated similar associations of ApoE type with AD: a direct association with ApoE4 and a less dramatic inverse association ApoE2. Advanced age did not appear to influence the ApoE4-AD association. The association with AD among ApoE4 homozygotes [odds ratio (OR) = 14.7] was higher than expected based on an observed OR of 2.0 in heterozygotes. Phenotype-genotype nonconcordance was more frequent for ApoE2 than for ApoE4. The ApoE2 phenotype occurred at a frequency of 7.9% vs a genotype frequency of 4.9%, corresponding to a probability of 56% that an individual with ApoE2 phenotype had the same genotype. Whereas E4 and E2 phenotypes and genotypes were comparably associated with AD, neither method would be expected to substantially improve the efficiency of case finding in the context of population screening beyond prediction based on age and education. Nonconcordance of phenotype and genotype was substantial for E2 and modest for E4 in this population. The ApoE4-AD association was independent of age.

LDL physical properties, lipoprotein and Lp(a) levels in acromegalic patients. Effects of octreotide therapy

High vascular morbidity and mortality is associated with acromegaly. The aim of the present study was to assess the effects of octreotide therapy on several known cardiovascular risk factors and to correlate them with octreotide-induced hormonal changes. Lipid levels, LDL particle size distribution as evaluated by single vertical spin density gradient ultracentrifugation, apolipoproteins AI and B, lipoprotein (a) [Lp(a)] concentrations and apo(a) phenotypes were evaluated in 20 non-diabetic acromegalic patients (6 M, 14 F), with normal thyroid, adrenal and gonadal function, aged 29–66 years. Normal subjects (20), matched for age, sex and BMI served as control for lipid variables. Acromegalic patients were characterized by lower HDL cholesterol (and apoA-I) and by higher Lp(a) concentrations in comparison to controls. Treatment with octreotide (100 μg t.i.d. for 3 months) led to: an increase in HDL cholesterol (median: +22%), a decrease in LDL cholesterol (−14%) and a decrease of the Lp(a) levels (all phenotypes) (−28%). The expected decreases of IGF-I levels (median: −48%) and 7-h AUC of GH (−50%), insulin (−40%), and glucagon (−20%) were observed. Only Lp(a) modifications showed a correlation with GH modifications. The study of LDL physical properties showed that acromegalic patients had smaller and/or more dense LDL particles, in comparison with normal controls (relative flotation rate, Rf: 0.40±0.03 versus 0.42±0.02 P<0.05), an alteration that might contribute to the high vascular risk of acromegalic patients. However, the LDL subfraction distribution remained unmodified during octreotide therapy (Rf 0.39±0.03). In conclusion, this study shows that in acromegalic patients octreotide treatment is indeed associated with an amelioration of some lipoprotein parameters, i.e. LDL, HDL, and Lp(a) concentrations. However, this treatment has no effect on the small and/or dense LDL particles present in these patients.

016 Type III hyperlipidaemia, related to PI treatment, is not caused by homozygosity for apoE2

Objective: To determine the prevalence of PI-induced Type III hyperlipidaemia and its relation with apoE2 homozygosity. Methods: Sixty-seven HIV+ patients on PI for a median of 26.5 months were tested for fasting cholesterol, triglyceride, HDL cholesterol, lipoprotein (a) and glucose. Lipoprotein electrophoresis was performed when cholesterol was > 6.5 mmol/L or triglyceride > 4.5 mmol/L. ApoE phenotype was determined using isoelectric focusing followed by Western blotting. Lipodystrophy was diagnosed clinically. Results: Fifty patients were dyslipidaemic 42 with triglyceride > 2.3 mmol/L, 32 with cholesterol > 6.5 mmol/L and 34 with HDL cholesterol < 0.9 mmol/L. 20 had a lipoprotein (a) > 300 mg/L. Sixteen patients had lipodystrophy. Eleven patients (19.3%) had a Type III hyperlipidaemia pattern, seven with associated lipodystrophy. Only one was homozygous for E2 phenotype and none had diabetes. Mean interval between the start of PI and dyslipidaemia was 240 days. Conclusion: Type III hyperlipidaemia is common in this group and unlike HIV-negative subjects is often not associated with the apo-E2/E2 isoform. HIV protease inhibitors may interfere with lipoprotein-receptor-related protein.

Apolipoprotein E ϵ4 and tardive dyskinesia in a Japanese population

The findings that free radicals play a causative role in the occurrence of tardive dyskinesia (TD) and that apolipoprotein E (ApoE) 4 has decreased anti-oxidant activity suggest a potential link between TD and ApoE alleles. We, therefore, examined ApoE allelic frequencies in schizophrenic subjects with TD and non-TD. Serum samples were obtained from 333 DSM IV-diagnosed schizophrenic patients and 191 controls in Japan. The presence of TD was evaluated by research diagnostic criteria for TD. ApoE phenotypes of the serum samples were determined by polyacrylamide gel isoelectricfocusing. A total of 62 TD subjects (31 males, 31 females) were identified among all patients examined. No significant differences in ApoE allelic frequency were found between TD and non-TD groups. ApoE ϵ4 allele frequency, however, was significantly lower in the female TD group than in the male TD group. These findings do not clearly demonstrate a certain association between TD and the ϵ4 allele, but may preliminarily reveal a difference in influence of this allele on the development of TD between males and females.

The apolipoprotein E ε4 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.

The role of lipoprotein[a] in atherosclerosis.

Recent studies confirm and extend previous evidence that lipoprotein (Lp) plays a significant role in atherosclerosis and is one of the top five or six risk factors for cardiovascular disease. In Japanese patients, Lp levels and apo phenotypes are significant predictors for myocardial infarction. Lp levels are significantly higher in ischemic stroke patients than in controls. However, plasma concentrations of Lp are not predictive of ischemic cerebral infarction in either men or women. Serum Lp levels are significantly higher in patients with carotid plaques or measurable intima-media thickness than in controls without. Despite these associations, there is no significant relationship between Lp level and arterial endothelial function, smooth muscle response, or carotid wall thickness, even though other lipid risk factors like low-density lipoprotein cholesterol (LDL-C) and LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio are correlated with abnormal arterial function and structure. There is new evidence that the association of Lp with extracellular matrix (ECM) secreted by arterial smooth muscle cells increases two- to threefold the subsequent specific binding of LDL. Alpha-defensins released from activated or senescent neutrophils stimulate the binding of Lp to ECM of endothelial cells. Several factors that affect the accumulation of Lp and oxidized LDL in the arterial intima have been identified. Several recent studies have provided new insights into the physiologic role that Lp might play in compromising fibrinolysis. The interaction of Lp with cells is clearly distinct from that with ECM and with fibrinogen; the regulation sites within Lp and plasminogen for these regulatory molecules are not identical. These recent advances bring us significantly closer to understanding how Lp exerts its atherogenic and thrombogenic properties.