Association of APOE epsilon2/epsilon3/epsilon4 and promoter gene variants with dementia but not cardiovascular mortality in old age.

The common apolipoprotein E (APOE) alleles epsilon2, epsilon3, and epsilon4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (- 219G/T and -491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population-based cohort of 648 subjects aged 85 years and over (Leiden 85-Plus Study). Genotypes containing an APOE epsilon4 allele were associated with a 4.1-fold (95% CI, 2.2-7.7) increased risk of dementia as compared to the epsilon3/epsilon3 genotype in old subjects. Moreover, homozygosity for the -219T allele was found to be associated with a 2.4-fold (95% CI, 1.0-5.8) increased risk independently of epsilon2 and epsilon4; the -491A/T variant was not associated with dementia. Over a 10-year follow-up period, the risk of cardiovascular mortality was not increased among epsilon4 carriers (RR, 0.6; 95% CI, 0.4-1.0) or -219T homozygous subjects (RR, 1.1; 95% CI, 0.7-1.7), nor did it decrease among -491T homozygous subjects (RR, 1.4; 95% CI, 0.6-3.1). In conclusion, both the APOE epsilon2/epsilon3/epsilon4 and the -219G/T variant were identified as risk factors for dementia but not cardiovascular mortality in old age. Our results support the hypothesis that both the isoform and the amount of APOE may influence the risk of dementia. Furthermore, they emphasize that variation at the APOE locus has a higher impact on the risk of dementia than on the risk of cardiovascular disease in old age.     

The CDC2 I-G-T haplotype associated with the APOE epsilon4 allele increases the risk of sporadic Alzheimer's disease in Sicily

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.     

Depression, APOE genotype and subjective memory impairment: a cross-sectional study in an African-Caribbean population

BACKGROUND: Subjective memory impairment (SMI) is common in older populations but its aetiology and clinical significance is uncertain. Depression has been reported to be strongly associated with SMI. Associations with objective cognitive impairment are less clear cut. Other factors suggested to be associated with SMI include poor physical health and the apolipoprotein E (APOE) epsilon4 allele. Studies of SMI have been predominantly confined to white Caucasian populations. METHOD: A community study was carried out in a UK African-Caribbean population aged 55-75, sampled from primary care lists. Twenty-three per cent were classified with SMI. Depression was defined using the 10-item Geriatric Depression Scale. Other aetiological factors investigated were education, objective cognitive function, APOE genotype, disablement and vascular disease/risk. The principal analysis was restricted to 243 participants scoring > 20 on the Mini-Mental State Examination (85%). A second analysis included all 290 participants. RESULTS: Depression, self-reported physical impairment and APOE epsilon4 were associated with SMI. The association between SMI and physical impairment was not explained by depression, vascular disease/risk, or disability/handicap. The association between epsilon4 and SMI increased as MMSE scores decreased and was particularly strong in those with depression. The epsilon4 allele was present in 69% (95% CI 41-89%) of those with depression and SMI compared with 28% (20-36%) of those with neither. CONCLUSIONS: Depression may not be a sufficient explanation for subjective memory complaints. Memory complaints in the presence of depression are associated with high prevalence of epsilon4 and therefore, presumably, a raised risk of subsequent dementia.     

The association between delirium and the apolipoprotein E epsilon4 allele in the elderly

OBJECTIVE: As not all patients with similar risk factors and eliciting conditions develop delirium; it may be hypothesized that genetic variation may play a role in the risk of delirium. On the basis of the relationship between dementia, respectively reduced cholinergic activity, and the APOE epsilon4-allele, and the similarities between dementia and delirium in reduced cholinergic activity, the APOE epsilon4-allele is a rational candidate-gene for delirium. This study examined the association between APOE epsilon4-allele and delirium in elderly patients. METHODS: Acutely admitted patients to the Department of Medicine of 65 years and over were included during a 27-month time period. Delirium was scored by the confusion assessment method. Cognitive impairment was diagnosed by Mini Mental State Examination and informant questionnaire on cognitive decline. Genotyping was done with matrix-assisted laser-desorption/ionization time-of flight mass spectrometry. RESULTS: Of 415 included patients, a random sample of 264 patients was genotyped for APOE. The patients who met the criteria for delirium (35%) were significantly older and more frequently had preexisting functional and cognitive impairment. APOE genotype was borderline significantly associated with cognitive impairment in patients below 75 years (P=0.057). The odds ratio for carriers of an APOE epsilon4-allele compared with patients without an APOE epsilon4-allele for developing delirium was 1.17 (95% confidence interval (CI): 0.49-2.78) in the cognitively intact patients and 0.42 (95% CI: 0.14-1.30) in the cognitively impaired patients. No relation existed between the total number of APOE epsilon4-alleles and the different delirium subtypes (P=0.12). CONCLUSIONS: We found no convincing evidence that carriers of the APOE epsilon4-allele have a higher risk of delirium.     

Education halves the risk of dementia due to apolipoprotein ε4 allele: a collaborative study from the Swedish Brain Power initiative

A number of studies have explored the relationships of apolipoprotein E (APOE) genotype and education with dementia over the last decade. However, observations concerning the possible modifying effect of education on the APOE-dementia association are limited. The objective of this study was to test the hypothesis that education may decrease the risk of APOE ε4 on dementia. Pooled data from 3 major population-based studies in Northern Europe were used in this study, with a total of 3436 participants aged 65 and older derived from the Kungsholmen project and the Gothenburg Birth Cohort studies in Sweden, and the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) project in Finland. The main outcome measure was dementia, which was diagnosed in 219 persons according to standard criteria. APOE ε4 was associated with increased risk of dementia independent of the effect of education (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.9-3.4 for 1 ε4 carrier and OR, 3.7; 95% CI, 1.8-7.2 for 2 ε4 carriers). High education (8 years and more) was related to a lower dementia risk (OR, 0.5; 95% CI, 0.3-0.6). An interaction between education and APOE ε4 was observed. Compared with those with less education and no ε4, the odds of dementia among persons with low education who carried any ε4 allele was 2.7 (95% CI, 1.9-3.9), and 1.2 (0.7-1.8) if they had higher education. This study suggests that genetic (APOE ε4) and environmental (education) factors are not only independently but also interactively related to dementia risk and that high education may buffer the negative effect of APOE ε4 on dementia occurrence.     

Common variation in GRB-associated Binding Protein 2 (GAB2) and increased risk for Alzheimer dementia

GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onset Alzheimer dementia (AD) risk in carriers of the APOE epsilon4 allele in a genome-wide association analysis. We aimed to investigate this association in a well-characterized Belgian late-onset AD patient/control group: 528 Belgian AD patients (mean onset age 79.0+/-5.2 years, 70.2% females) and 601 ethnically matched control individuals (mean age 61.9+/-15.3 years, 57.1% females) were genotyped for 10 SNPs across the GAB2 locus. For 2 SNPs the most common genotype was associated with risk for AD, with the most significant result for rs4945261 [OR 1.49 (95%CI 1.04-2.15)]. After stratification by presence or absence of APOE epsilon4 these associations were present in APOE epsilon4 carriers only. When assessing the effect of APOE and rs4945261 in one model, rs4945261 did not show a main effect, but the joint risk effect of rs4945261-GG and APOE epsilon4 on AD was significant (OR 3.87, 95%CI 2.66-5.63; p=1.0E-12), with a deviation of 1.87 from the multiplicative model of interaction. Haplotype analyses showed evidence of association in the total (global p(sim) 0.04) and APOE epsilon4+ (global p(sim) 0.02) but not in the APOE epsilon4 - group (global p(sim) 0.6). The association was driven by a higher frequency of the major haplotype in patients. Our data independently replicate an association between GAB2 and late-onset AD, which appears to be limited to APOE epsilon4 carriers.     

TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels

Alzheimer disease (AD), vascular dementia, and stroke are all associated with inflammation though their respective initiating factors differ. Recently a polymorphism in the proinflammatory cytokine tumor necrosis factor (TNF), in association with apolipoprotein E (APOE), was reported to increase AD risk. Two SNPs, rs1799724 (-850C>T; NT_007592.14:g.22400733C>T) and rs1800629 (-308G>A; [NT_007592.14:g.22401282G>A]), and the APOE polymorphism were genotyped in 506 patients with sporadic AD and in 277 cognitively healthy controls. In a subset of 90 individuals we also investigated whether these SNPs exerted any functional effects on cerebrospinal fluid (CSF) beta-amyloid (Abeta) levels. The frequency of the rs1799724 genotypes and the rs1799724-T allele were significantly different in AD individuals (P=0.009; odds ratio [OR], 1.63; 95% confidence interval [CI], 1.13-2.34), while the rs1800629 SNP was not associated with AD. Significant interaction was observed between the rs1799724-T and APOE epsilon4 alleles in that the rs1799724-T allele significantly modified risk associated with possession of the epsilon4 allele only (epsilon4 in absence of rs1799724-T: OR, 2.92; 95% CI, 2.00-4.27; epsilon4 in presence of rs1799724-T: OR, 6.65; 95% CI, 3.26-13.55; P=0.03). Haplotyping analysis revealed a significant overrepresentation of an rs1799724-T/rs1800629-G haplotype in AD (P=0.012; OR, 1.60; 95% CI, 1.11-2.29), although to a lesser degree than rs1799724-T alone. Further, the rs1799724-T allele was found to be associated with lower levels of CSF Abeta42 (P=0.023), thus corroborating the genetic findings. Inheritance of the rs1799724-T allele appears to synergistically increase the risk of AD in APOEepsilon4 carriers and is associated with altered CSF Abeta42 levels. Further investigations are warranted to assess the significance of these novel findings.     

Butyrylcholinesterase K variant is genetically associated with late onset Alzheimer's disease in Northern Ireland

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been associated, sometimes controversially, with polymorphisms in a number of genes. Recently the butyrylcholinesterase K variant (BCHE K) allele has been shown to act in synergy with the apolipoprotein E epsilon4 (APOE epsilon4) allele to promote risk for AD. Most subsequent replicative studies have been unable to confirm these findings. We have conducted a case-control association study using a clinically well defined group of late onset AD patients (n=175) and age and sex matched control subjects (n=187) from the relatively genetically homogeneous Northern Ireland population to test this association. The BCHE genotypes of patients were found to be significantly different from controls (chi(2)=23.68, df=2, p<0.001). The frequency of the K variant allele was also found to differ significantly in cases compared to controls (chi(2)=16.39, df=1, p<0.001) leading to an increased risk of AD in subjects with this allele (OR=3.50, 95% CI 2. 20-6.07). This risk increased in subjects 75 years and older (OR=5. 50, 95% CI 2.56-11.87). At the same time the APOE epsilon4 associated risk was found to decrease from 6.70 (95% CI 2.40-19.04) in 65-74 year olds to 3.05 (95% CI 1.34-6.95) in those subjects 75 years and older. However, we detected no evidence of synergy between BCHE K and APOE epsilon4. The results from this study suggest that possession of the BCHE K allele constitutes a significant risk for AD in the Northern Ireland population and, furthermore, this risk increases with increasing age.     

APOE, ACT and CHRNA7 genes in the conversion from amnestic mild cognitive impairment to Alzheimer's disease

We have investigated whether the -86 C/T promoter polymorphism in CHRNA7 gene, the signal peptide polymorphism of the alpha1-antichymotripsin (ACT) gene or the APOE genotype are associated with an increased risk of mild cognitive impairment (MCI) or affect the risk of evolution to Alzheimer's disease (AD). We have followed up 89 patients with initial diagnoses of amnestic MCI for 49 months. Patients were separated into three groups: 27 subjects who remained with MCI, 40 that converted to AD before 20 months and 22 that converted to AD after. To assess the risk associated to each genotype a control group (n=90) without cognitive impairment was included. APOE4 allele was associated with an increased risk of MCI (OR: 6.04, 95% CI: 2.76-3.23; p<0.001) but did not have an effect on the probability of evolving AD. ACT or CHRNA7 genotypes were not associated with MCI but both appear to modify the risk of progression to dementia in opposing manners: ACT polymorphism increasing the risk to evolve to AD before 20 months (HR=2.03; 95% CI: 1-4.6; p=0.06) and CHRNA7 polymorphism protecting from evolution to dementia. Cox regression model demonstrated that ACT genotype confers a higher risk of rapid evolution to dementia than age or years of schooling. We conclude that APOE is a risk gene for amnestic MCI and that ACT and CHRNA7 may act in these patients as modifier genes for the time of progression to AD.     

The effects of APOE and tau gene variability on risk of frontotemporal dementia

Frontotemporal dementia (FTD) is a complex dementing syndrome whose genetic/non genetic risk factors are mostly unknown. Aim of the present work was to investigate whether APOE and/or tau gene variability does affect the risk of FTD. A sample of FTD cases (sporadic: n = 54; familial: n = 46, one subject per family) was collected in a genetically homogeneous population (Calabria, southern Italy) and analyzed in comparison with an age- and sex-matched control group (n = 180) extracted from the same population. Logistic regression analysis showed that APOE gene variability affects the probability of disease, with allele epsilon4 increasing (exp(beta1) = 2.68 with [1.51-4.76] 95% confidence interval; p = 0.001) and allele epsilon2 decreasing (exp(beta1) = 0.28 with [0.12-0.66] 95% confidence interval; p = 0.003) the risk of FTD. On the contrary, tau gene variability was ineffectual (exp(beta1) non significantly different from 1 for either H1 or H2 haplotypes), although a small effect was observed by the H1 haplotype in increasing the protective effect of the epsilon2 allele (p = 0.007).     

Apolipoprotein gene E4 allele promoter polymorphisms as risk factors for Alzheimer's disease

Alzheimer's disease is a complex neurodegenerative disorder, characterized by progressive cognitive decline and distinct neuropathology. The apolipoprotein gene E4 allele (APOE 4) is a major risk factor for the disease. Promoter polymorphisms at -491 and -427 may also contribute to the risk. We examined the two polymorphisms in 178 Alzheimer's patients and 141 controls. The -491AA genotype was overrepresented among the patients (68 versus 54%, P=0.01). However, in patients who were APOE4 carriers, the -491AA genotype more than doubled the risk [odds ratio (OR)=2.5; 95% confidence interval (CI)=1.2-5.4], especially in combination with -427TT [odds ratio (OR)=3.3; 95% confidence interval (CI)=1.5-7.7]. Moreover, the -491A/-427T/APOE4/APOC1A haplotype was threefold higher for patients. These results contribute to the evidence that regulation of APOE4 expression modulates risk for Alzheimer's disease.     

Association of a dopamine beta-hydroxylase gene variant with depression in elderly women possibly reflecting noradrenergic dysfunction

BACKGROUND: Depression has a multifactorial etiology which involves genetic factors and comorbid diseases. METHODS: A cross-sectional sample of 1371 elderly women (mean age=69.2 years) was examined. Detailed information on their health was obtained. Cognitive functions were assessed by the Short Blessed Test and the Animal Naming Task. A 19 bp insertion/deletion polymorphism in the dopamine beta-hydroxylase (DBH) gene, the apolipoprotein (APOE) epsilon2/epsilon3/epsilon4 variation and 5-HTTLPR in the serotonin transporter gene were genotyped. RESULTS: Depression was univariately associated with homozygosity for the DBH gene 19 bp deletion allele (odds ratio [OR]=1.96, 95% confidence intervals [95% CI]=1.17-3.29, p=0.01), family history of depression (OR=3.86, 95% CI=1.85-8.06, p=0.0003), a composite measure of cardiovascular diseases (OR=1.96, 95% CI=1.11-3.47, p=0.02), cognitive impairment assessed by the Short Blessed Test (OR=3.88, 95% CI=1.29-11.64, p=0.02) and performance on the Animal Naming Task (OR=0.74, 95% CI=0.59-0.93, p=0.01). The strength of the association of DBH genotype with depression essentially remained unchanged after correction for other variables in a multivariate model. This association may reflect noradrenaline dysfunction in the brain.     

Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to age-matched controls

Alzheimer disease (AD) is an emotionally devastating and exceptionally costly disease. Apolipoprotein E (APOE) is a major risk factor gene for AD regardless of age of onset or family history. However, this association may not be as strong or consistent in ethnic groups such as African Americans, raising the possibility of other modifier gene(s). In a group of African American AD patients, a significantly increased risk of AD was associated with two E4 alleles (OR = 5.6; 95% CI = 1.5-21.0) or one E4 allele (OR = 2.5; 95% CI = 1.3-5.0) when compared to E3/E3 genotype, and there was a significant lowering of age of onset for affecteds with E4/E4 genotype as compared to one E2 allele (P = 0.02) or all others (P = 0.03). We also found a significant increase in age of onset with the -308 #2 (A) allele of TNF when compared to AD cases with no #2 allele. A significant increase in age was also demonstrated with the #2 allele (99 base pairs) of the microsatellite TNFa, located approximately 10.5 kb upstream of TNF. When these two alleles were combined with the TNF -238G (#1) allele to give a haplotype, the significant increase in age was still demonstrated. Polymorphisms in the APOE promoter and six other candidate genes did not appear to demonstrate any significant association with our African American AD patients. Our results confirm the established association of APOE4 to AD observed in several ethnic groups, including African Americans. In addition, TNF appears to have some modifying effect in AD, primarily on age of onset, or it could be in linkage disequilibrium with a modifier locus nearby.     

Type 2 diabetes mellitus and its renal complications in relation to apolipoprotein E gene polymorphism

The apolipoprotein E (APOE) epsilon2 allele is reported to be associated with greater risk of renal impairment in type 2 diabetes. Relationships among APOE polymorphisms, renal impairment, and biochemical parameters were explored. A prospective study of 405 consenting Chinese type 2 diabetic patients [mean age +/- standard deviation (SD): 59.2 +/- 10.3 years] without advanced complications at entry was conducted. APOE genotyping and measurement of plasma biomarkers of oxidative stress and antioxidants were performed at entry. HbA1C, plasma glucose, lipids, creatinine, urine albumin/creatinine, and blood pressure were measured at entry and at up to 4 years of follow-up. APOE allelic frequencies were in Hardy-Weinberg equilibrium. Odds ratios of albuminuria at entry and/or during follow-up for different APOE groups were not significantly different. The non-epsilon2 (epsilon3/3, epsilon3/4, epsilon4/4) group had significantly greater plasma ascorbate (51.6 +/- 20.1 mumol/L) than the epsilon2 (epsilon2/2, epsilon2/3) group (44.5 +/- 16.2 mumol/L, P = 0.021), but higher plasma ascorbate levels did not seem to decrease the risk of renal impairment in the non-epsilon2 group. Baseline plasma lipid-standardized alpha-tocopherol levels were least in epsilon2 subjects with persistent albuminuria (3.6 +/- 1.1 mumol/mmol of total cholesterol plus triglycerides, P = 0.008) compared with epsilon2 subjects who had no albuminuria at entry or during follow-up (4.5 +/- 0.8 mumol/mmol of total cholesterol plus triglycerides). The APOE epsilon2 allele does not seem to be associated with increased risk of renal impairment in Chinese type 2 diabetic patients. Plasma lipid-standardized alpha-tocopherol may play a role in determining risk of renal dysfunction in type 2 diabetes.     

Coupling phenomena during asynchronous submaximal two-hand,multi-finger force production tasks in humans

Since a deletion/insertion polymorphism in the promoter region of the apolipoprotein C-I (APOC1) gene has been reported to be associated with late-onset Alzheimer's disease (LOAD), we examined the hypothesis in a Korean population with 120 LOAD cases and 132 age-matched controls. The frequency of APOC1 insertion allele (H2) was significantly increased in LOAD than in controls, giving an odds ratio of 3.3 (95% CI 2.0-5.5, P<0.0001). Logistic regression analysis revealed that the interaction model between APOE epsilon4 and APOC1 H2 yielded larger odds ratio than other models including either APOE epsilon4 or APOC1 H2 alone. In addition, the association between APOC1 H2 and LOAD remained significant after adjustment of the effect of APOE epsilon4 (P=0.036). These results support previous observations that the APOC1 might be an additional susceptibility gene for LOAD.     

Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease

The allelic frequency of the gene for the K variant of butyrylcholinesterase (BCHE-K) was 0.17 in 74 subjects with late-onset (age > 65 years) histopathologically diagnosed Alzheimer's disease (AD), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07) and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the epsilon 4 allele of the apolipoprotein E gene (APOE), among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 (95% C.I. 1.65-29) in subjects > 65 years and of 12.8 (1.9-86) in subjects > 75 years. In APOE epsilon 4 carriers over 75 years, only 1/22 controls, compared with 10/24 confirmed late-onset AD cases, had BCHE-K. We suggest that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon 4 as a susceptibility gene for late-onset AD.      

Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes

The epsilon4 haplotype of APOE is the only undisputed genetic risk factor for late-onset Alzheimer's disease (LOAD). It has been proposed that at least two other polymorphisms in the promoter of the APOE gene (-219G>T and -491A>T) might also contribute to disease susceptibility, and modulate the impact of structural changes in the ApoE protein, by altering its expression. In order to assess the extent of cis-acting influences on APOE expression in human brain, highly quantitative measures of allele discrimination were applied to cortical RNA from individuals heterozygous for the epsilon alleles. A small, but significant, increase in the expression of epsilon4 allele was observed relative to that of the epsilon3 and epsilon2 alleles (P<0.0001). Similar differences were observed in brain tissue from confirmed LOAD subjects, and between cortical regions BA10 (frontopolar) and BA20 (inferior temporal). Stratification of epsilon4/epsilon3 allelic expression ratios according to heterozygosity for the -219G>T promoter polymorphism revealed significantly lower relative expression of haplotypes containing the -219T allele (P=0.02). Our data indicate that, in human brain, most of the cis-acting variance in APOE expression is accounted for by the epsilon4 haplotype, but there are additional, small, cis-acting influences associated with promoter genotype.     

Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study

Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three common isoforms: APOE2, -3 and -4. The varepsilon4 allele of the APOE gene ( APOE ) coding for the APOE4 isoform is associated with an increased risk of myocardial infarction (MI) and of Alzheimer's disease (AD). Recently, several polymorphisms in the APOE regulatory region have been reported. Some of these have been associated with AD and modified APOE allelic mRNA expression in AD brains. Here, we have investigated whether three of these promoter polymorphisms (-491AT, -427CT and -219GT) can also modify cardiovascular risk. The hypothesis was tested in a large multicentre case-control study of MI, the ECTIM Study, on 567 cases and 678 controls. Among the three APOE promoter polymorphisms tested, only the-219T allele was associated with a significantly increased risk of MI (OR = 1.29, 95% CI: 1.09-1.52, P < 0.003) and the effect was shown to be independent of the presence of the other mutations, including the APOE epsilon2/epsilon3/epsilon4 polymorphism. Moreover, the-219T allele greatly decreased the APOE plasma concentrations in a dose-dependent manner ( P < 0.008). These data indicate that the-219GT polymorphism of the APOE regulatory region emerges as a new genetic susceptibility risk factor for MI and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases.     

Heparan sulfate proteoglycan 2 polymorphism in Alzheimer's disease and correlation with neuropathology

A genetic association of an intronic single nucleotide polymorphism site of heparan sulfate proteoglycan 2 (HSPG2) with Alzheimer's disease (AD) was investigated among Finnish AD patients (n=213) and controls (n=269). No association of the HSPG2 polymorphism alone was observed with AD. However, an association of HSPG2 A allele with AD was detected in apolipoprotein (APOE) epsilon4 allele carriers. The odds ratio for AD was doubled in subjects carrying both epsilon4 and HSPG2 A alleles (OR=6.6) when compared to subjects with epsilon4 allele alone (OR=3.1). The impact of HSPG2 polymorphism on beta amyloid and tau pathology was studied using immunohistochemistry. Paired helical filament labeling was significantly more pronounced in AD patients carrying both epsilon4 and HSPG A alleles when compared to epsilon4 carriers lacking the HSPG2 A allele. In conclusion, HSPG2 A allele may possess an additive risk effect among the APOE epsilon4 carriers in AD.     

Apolipoprotein E epsilon 4 affects new learning in cognitively normal individuals at risk for Alzheimer's disease

The Apolipoprotein E (APOE) epsilon 4 allele is an important risk factor for Alzheimer's disease (AD). Given the interest in early identification of at-risk individuals, we examined memory decline as a function of APOE status and age in cognitively intact participants aged 48-77 years old (yo). Participants were grouped by age (<60 versus > or =60) and APOE (epsilon4+/-). Longitudinal analysis of several components of memory over a 2-year interval showed a significant Age-by-APOE interaction reflecting a decline in new learning for the > or =60 epsilon4+ group only. Among epsilon4+, 76% of the > or =60 participants showed a decline versus 32% of the <60, but the amount of decline in new learning over the 2-year interval within the > or =60 group was not further influenced by age. That is, the size of the 2-year change was the same for 60 and 70 year old participants. This suggests that longitudinal study of new learning is a sensitive measure for detecting early cognitive changes in at-risk individuals that precede the symptomatic onset of mild cognitive impairment and AD.