APOE Epsilon4 Allele Research Articles

17 Education Moderates the Association Between Hippocampal CBF and Memory in Women but Not Men

Objective:Higher educational attainment is associated with reduced risk for Alzheimer's disease (AD) dementia, and its protective effect may act through alterations in cerebral blood flow (CBF) that allow for better coping with accumulating neuropathology. Additionally, there are sex differences in both the risk of developing AD as well as the potential protective effects of education. We therefore sought to investigate whether education moderates the association of hippocampal CBF and memory in cognitively unimpaired older adults, and to examine if these interactions were moderated by sex.Participants and Methods:Cognitively unimpaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 51 men, 50 women) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify bilateral hippocampal CBF. Sex was defined as sex at birth. Multiple linear regressions assessed (1) the independent associations among education, CBF, and memory performance separately in men and women and (2) the three-way interactions among CBF, sex, and education, followed by sex-stratified analyses. Three outcome measures were examined: Logical Memory Story A immediate and delayed recall, and Rey Auditory Verbal Learning Test (RAVLT) intrusions. All models adjusted for age and APOE epsilon-4 allele frequency, and all models with CBF additionally adjusted for cerebral metabolism (baseline FDG-PET composite) and pulse pressure.Results:CBF was not associated with education or memory in either women or men. There was a positive association between education and delayed memory in women (ß=0.14, t=2.64, p=0.008) as well as trending, positive associations between education and immediate memory in women (ß=0.09, t=1.79, p=0.074) and education and delayed memory in men (ß=0.09, t=1.94, p=0.054). Three-way interactions among sex, CBF, and education were significant on immediate recall (ß=2.55, t=2.53, p=0.013), delayed recall (ß=2.56, t=2.44, p=0.017), and RAVLT intrusions (ß=-2.28, t=-2.27, p=0.026). In women, there were interactions between education and hippocampal CBF on both immediate (ß=2.49, t=2.90, p=0.006) and delayed recall (ß=2.30, t=2.78, p=0.009), such that as education increased, the strength of the association between CBF and immediate memory increased. There was also an interaction between education and hippocampal CBF on RAVLT intrusions in women (ß=-2.42, t=-3.05, p=0.004), such that as education increased, the strength of the association between CBF and number of intrusions decreased; there was a main effect where in women with lower education, as CBF increased, the number of intrusions increased (ß=0.76, t=2.59, p=0.032); in women with higher education, there was no association between CBF and intrusions. In men, none of these two-way interactions were significant.Conclusions:These results suggest that, in cognitively unimpaired older women, the relationship between hippocampal CBF and memory is moderated by education level, even when adjusting for several other factors. Specifically, higher education may serve as a protective factor in the hippocampal CBF-memory relationship, and this relationship was sex-dependent, occurring in women only. Further research is needed to examine these relationships longitudinally across the clinical continuum of AD. Additionally, this work needs to be conducted in more diverse samples to allow for analyses investigating the impact of education on the intersection of race/ethnicity and sex/gender.

Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals at risk for Alzheimer's disease: A 31Phosphorus MR spectroscopy study.

Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer's disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men's brains to a similar metabolic range as women's brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

The effects of ApoE epsilon4 alleles on cognitive function and resting-state functional MRI in patients with amnestic mild cognitive impairment: a prospective cohort study

Objective To explore the effects of ApoE epsilon4 (ApoE-e4) alleles on cognitive function and resting-state functional MRI (rs-fMRI) in patients with amnestic mild cognitive impairment(aMCI) based on a prospective cohort study. Methods An average of 20 months of prospective observations were conducted on 16 ApoE-e4-carriers and 24 non-carriers of aMCI. Neuropsychological assessments and rs-fMRI data were collected at both baseline and follow-up. All participants were assessed by a battery of neuropsychological tests and underwent rs-fMRI. Two core regions of the default mode network (DMN), the left posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC), were selected as seeds to calculate the functional connectivity. Two-way repeated measures analysis of variance was used to assess the effects of ApoE genotype(e4-carriers, none4-carriers), interval and the interaction between these two factors for functional connectivity extracted from changed region found by t-test.Conversion rates of dementia were compared between ApoE-e4-carriers and none4-carriers at follow-up using Chi-square test. For the comparison of functional connectivity and clinical data between ApoE-e4-carriers and nonse4-carriers in baseline and follow-up, the normal distribution test was carried out first. If the normal distribution was fitted, the two-sample t test was used, otherwise, the Mann-Whitney rank sum test was used. Finally, the general linear model was used to assess the relationships between alterations in functional connectivity and in neuropsychological assessments as well as the interaction effect. Results (1)Significant decline in memory domains were found in ApoE-e4-carriers as compared to non-carriers at both baseline and follow-up. The ApoE-e4-carriers (14/16) presented a higher conversation rate than non-carriers(13/24, χ2=4.862, P=0.027) at follow-up. (2)Functional imaging analysis revealed that ApoE-e4-carriers exhibited significantly higher functional connectivity between the left PCC and the left angular (ApoE-e4-carriers: 0.23±0.11, non-carriers: -0.03±0.13, t=4.800, cluster size: 1 944 mm3, P=0.004), and between the left mPFC and the left angular (ApoE-e4-carriers: 0.33±0.21, non-carriers: 0.08±0.18, t=5.040, cluster size:1 836 mm3, P=0.006) as compared to non-carriers at follow-up. We detected significant effect for the interaction interval by ApoE-e4 on functional connectivity between the left angular and the left PCC (F=10.833, P=0.002)as well as the left mPFC (F=7.280, P=0.010). (3)The alteration of functional connectivity value between the left mPFC and the left angular in ApoE-e4-carriers was positively correlated with the changes ofimmediate memory (r=0.692, P=0.018). The correlation was not statistically significant in ApoE-e4-noncarriers (r=-0.198, P=0.417) and the integration effect was significant (F=8.632, P=0.006). Conclusions The ApoE-e4 actually accelerates the deterioration of cognitive function in aMCI patients and carriers presented relatively reserved functional connectivity between the left angular and other core regions within DMN, which indicated the disruption of functional connectivity may be one of the underline mechanisms of ApoE-e4 during AD process. Key words: Alzheimer disease; Cognition disorders; Apolipoprotein E3; Magnetic resonance imaging; Neural networks (computer)

The nitric oxide synthase-3 codon 298 polymorphism is not associated with late-onset sporadic Alzheimer's dementia and Lewy body disease in a sample from Hungary.

An association study was performed between apolipoprotein E (apoE) polymorphism and the common structural polymorphism Glu/Asp at codon 298 of the nitric oxide synthase (NOS3) gene in late-onset sporadic Alzheimer's dementia probands (LOAD), diffuse Lewy body dementia cases (DLBD) and controls in a Hungarian sample. The frequency of individuals who carried the apoE epsilon4 allele was significantly more common in both dementia groups (LOAD, 20%; DLBD, 27%; control, 8%; control versus DLBD, chi2=13.264, degrees of freedom=2, P<0.001; control versus LOAD, chi2=6.628, degrees of freedom=2, P<0.036). However, there were no significant differences in the NOS3 genotype and allele distributions between the LOAD, DLBD and control groups. The apoE status has been found to be independent from the NOS3 codon 298 polymorphism in the examined cohort. Despite the facts that NOS3 is associated with neuritic sprouting, and aberrant neuronal and glial expression of the same molecule has been found in neurodegenerative diseases, it is unlikely that the polymorphism Glu/Asp of the NOS3 gene is involved in the development of LOAD and DLBD.

Admixture Analysis of Age at Onset in Alzheimer's Disease: Effect of the APOE epsilon4 allele

In Alzheimer's disease (AD) patients, the age at onset ranges from 40 to 90. By manuals, AD patients who develop symptoms before the age of 65 are classified as Early Onset. The cut-off at 65 is arbitrary and unlike other neuropsychiatric conditions, such as obsessive-compulsive disorder, bipolar disorder and schizophrenia, in AD the age at onset was supported by clinical observations without any statistical validation.

Abstract 18767: Association of Protein-Coding Genetic Variants with Coronary Arterial Calcification in 21,000 Individuals of European and African Ancestries

Introduction: Coronary arterial calcification (CAC) is a marker of subclinical atherosclerosis in asymptomatic individuals, and is a heritable risk factor that correlates with the risk of coronary artery disease (CAD) development. Genotyping protein-coding regions of the genome with an array is a scalable approach to potentially discover causal low-frequency and rare protein-coding mutations with large phenotypic effects. Methods: Using the Illumina HumanExome BeadChip, we genotyped 247,870 variants (of which 231,539 are in exons) in each of 17,953 participants of European ancestry and 3,078 participants of African ancestry without clinical CAD from the Diabetes Heart Study, Framingham Heart Study, Family Heart Study, Cardiovascular Health Study, Rotterdam Study, Age Gene/Environment Susceptibility Study, Multi-Ethnic Study of Atherosclerosis, Dutch &amp; Belgian Lung Cancer Screening Trial, Young Finns Study, Gene Study of Atherosclerosis Risk in Families, High Risk Plaque Bioimage Study, Old Order Amish Study, and Jackson Heart Study. We tested whether protein-coding variants, individually or aggregated within a gene, were associated with CAC, both as a continuous and binary variable. Results: We first robustly replicated prior CAC genomic non-coding association signals at 9p21 (p=9.85 x 10-29) and PHACTR1 (p=4.10 x 10-23) identified in GWAS based on HapMap imputation. A rare nonsynonymous variant in APOB (rs5742904) was associated with increased CAC (p=1.01 x 10-10) although this signal was driven by the Old Order Amish where it is a known founder mutation. The nonsynonymous APOE rs7412 variant (maf=0.078), the APOE epsilon2 allele, was associated with reduced CAC (p=2.61 x 10-9). Additionally, there was evidence of association for the nonsynonymous SSTR3 rs4988466 variant (maf=0.046) (p=7.77 x 10-8). SSTR3 is involved in cell proliferation, among other functions. Gene-based burden approaches did not yield statistically significant associations. Conclusions: We discovered nonsynonymous coding variants in APOB, APOE, and SSTR3 associated with CAC in a meta-analysis approach of 21,000 individuals using an exon-enriched genotyping array.

Biochip for determination of genetic markers of sporadic Alzheimer’s disease risk in the Russian Slavic population

A biological microchip (biochip) for the genetic predis- position to sporadic form of Alzheimer's disease studying has been developed. The biochip allows determina- tion of ten genetic polymorphisms within APOE, TOMM40, APOJ, EXOC3L2, GAB2, A2M, CR1, BIN1 and PICALM genes. The genotyping assay includes the amplification of loci of interest and further allele-specific hybridization of the fluorescent labeled amplicons with oligonucleotides immobilized on a biochip. Based on the results of genotyping of 166 patients and 128 controls APOE epsilon4 allele was found to be significantly associated with Alzheimer's disease susceptibility (OR = 2.275, 95% CI = 1.045-4.954,p = 0.034). Additionally, protective effects for the APOE epsilon2 allele and CLUT-allele (rs11136000) were observed (OR = 0.215, 95% CI = 0.090-0.516, p = 0.001 and OR = 0.679, 95% CI = 0.47-0.99, p = 0.042, respectively). Gene-gene interaction revealed two genotype combinations associated with Alzheimer's disease: APOE E3/E4 GAB2 G/G (OR = 2.49; CI = 1.43-4.32, p = 0.001) and APOE epsilon4 GAB2 G/G (OR = 3.55, CI = 1.23-10.24,p = 0.015). Based on the results of the combined multivariate analysis the algorithm for identifying of individuals at increased risk of Alzheimer's disease was developed.

Association of the Apolipoprotein E Variants with Susceptibility to Pregnancy with Preeclampsia

Apolipoprotein E (ApoE) polymorphism plays a significant role in the development of several diseases, but its role in the preeclampsia disease incidence is not clear. Therefore, the purpose of this study was to investigate the susceptibility of some pregnant women to preeclampsia. In a comparative cross-sectional study, the ApoE polymorphism genotypes were investigated in 100 patients with preeclampcia and 100 normal pregnant, using the polymerase chain reactions (PCR) analysis. Serum lipids and lipoproteins concentrations were also evaluated using the commercially available kits. The difference in distribution of the epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon3, epsilon3/epsilon4 and epsilon4/epsilon4 genotypes between patient subjects and controls was not significantly (p = 0.266). The data obtained for Apo epsilon4, epsilon2 and epsilon3 alleles in the patient group was not different significantly from those obtained for the control group (p = 0.220). The VLDL and TG levels of the patient group were higher significantly than controls (p < 0.01, p < 0.01 respectively). The data obtained for HDL concentration (52.2 +/- 16.1 g/dL) of the patient group was not different significantly from controls (49.4 +/- 12.5 g/dL). The difference between LDL concentration of patients with preeclampsia and controls was not significant. The cholesterol concentration of control subjects was not different significantly from patient subjects. The observed profiles of ApoE alleles and genotypes frequencies suggest that Apo E polymorphism does not play a major role in the development of preeclampsia. Nonetheless, the abnormal lipid profiles that we found in patients with preeclampsia may have a genetic explanation and/or contribution.

Use of cerebrospinal fluid biomarker analysis for improving Alzheimer's disease diagnosis in a non-specialized setting.

Low levels of amyloid-beta42 (Abeta42) and high total-tau (t-tau) or phosphorylated-tau (p181-tau) levels in cerebrospinal fluid (CSF) were shown to be characteristic for Alzheimer's disease (AD) patients and for mildly cognitively impaired (MCI) or non-demented individuals who will progress to AD. The goal of this study was to evaluate the benefit of CSF biomarker testing in a setting with no specialized dementia centers, in order to improve the accuracy of AD diagnosis and to identify individuals with incipient AD. Using ELISA assay we analyzed CSF Abeta42, t-tau and p181-tau levels among clinically diagnosed non-demented individuals, AD patients and individuals with uncertain dementia (n=36). CSF cut-off values of low Abeta42 (less than or equal to 530 pg/mL) and high t-tau (less than or equal to 350 pg/mL) or p181-tau (less than or equal to 52 pg/mL) were used to identify individuals with AD/MCI-CSF profile, regardless of clinical diagnosis. APOE genotyping was performed using PCR-RFLP method. In accord with previous studies we detected significantly decreased levels of CSF Abeta42 and increased tau and p181-tau levels in clinically diagnosed AD group vs. non-demented controls. CSF profiling identified individuals with a typical AD/MCI-CSF pattern in clinically referred non-demented group (9 percent) and among patients with uncertain dementia (41.7 percent). APOE epsilon4-allele was associated with the CSF biomarker changes typical for AD. This study shows that in a non-specialized setting CSF biomarker testing may be used as a screening tool for improving the accuracy of AD diagnosis and for predicting individuals with incipient Alzheimer's disease who need to receive further clinical follow-up.

The Influence of Apolipoprotein E Epsilon4 Polymorphism on qEEG Profiles in Healthy Young Females: A Resting EEG Study

The epsilon4 allele of the Apolipoprotein E (ApoE) gene has been linked to various neurological conditions and the aging process in the elderly. However, evidence has suggested that the influence of ApoE epsilon4 may commence in early life. This study examined the modulatory effects of ApoE epsilon4 on regional neural activity as well as inter-regional neural interactions in a young population aged 19-21. Blood samples and resting state eyes-closed EEG signals were collected from 265 healthy females, and stratified into two groups: epsilon4 carriers and non-carriers. The values of the log-transformed mean power of 18 electrodes and the mutual information of 20 channel pairs across delta, theta, alpha and beta frequencies were analyzed. Our connectivity analysis was based on information theory, which combined Morlet wavelet transform and mutual information calculation. Between-group statistics were performed by independent t-test. We notice a consistent trend across the brain, in which ApoE epsilon4 carriers possess lower regional power at the alpha band. The epsilon4 allele is also associated with lower regional power at the theta frequency in the left frontal and posterior brain regions. Functional connectivity analyses reveal a right-lateralized network that differentiates epsilon4 carriers and non-carriers, with lower connectivity strengths for the former. Our tonic EEG analyses complement those of previous reports in that the ApoE epsilon4 allele has a negative impact on regional neural synchronization and inter-regional neural interaction.

Altered brain white matter integrity in carriers of the APOE epsilon4 allele with late onset depression: A risk for Alzheimer's disease?

Altered brain white matter integrity in carriers of the APOE epsilon4 allele with late onset depression: A risk for Alzheimer's disease?

Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men

The APOE epsilon4 allele is an established risk factor for Alzheimer disease (AD), yet findings are mixed for how early its effects are manifest. One reason for the mixed results could be the presence of interaction effects with other AD risk factors. Increasing evidence indicates that testosterone may play a significant role in the development of AD. The aim of the present study was to examine the potential interaction of testosterone and APOE genotype with respect to hippocampal volume in middle age. Participants were men from the Vietnam Era Twin Study of Aging (n = 375). The mean age was 55.9 years (range 51-59). Between-group comparisons were performed utilizing a hierarchical linear mixed model that adjusted for the nonindependence of twin data. A significant interaction was observed between testosterone and APOE genotype (epsilon4-negative vs epsilon4-positive). Those with both low testosterone (> or =1 SD below the mean) and an epsilon4-positive status had the smallest hippocampal volumes, although comparisons with normal testosterone groups were not significant. However, individuals with low testosterone and epsilon4-negative status had significantly larger hippocampal volumes relative to all other groups. A main effect of APOE genotype on hippocampal volume was observed, but only when the APOE-by-testosterone interaction was present. These findings demonstrate an interaction effect between testosterone and the APOE epsilon4 allele on hippocampal volume in middle-aged men, and they may suggest 2 low testosterone subgroups. Furthermore, these results allude to potential gene-gene interactions between APOE and either androgen receptor polymorphisms or genes associated with testosterone production.

Failure to Replicate an Association of rs5984894 SNP in the PCDH11X Gene in a Collection of 1,222 Alzheimer's Disease Affected Patients

A recent genome-wide study on late-onset Alzheimer's disease identified a SNP (rs5984894) on Xq21.3 in the PCDH11X gene strongly associated with LOAD individuals of European descent from the United States. We genotyped the same polymorphism in 1222 cases and 938 controls from central-northern Italy and could not confirm the association on the Italian population: multivariate logistic regression adjusted for gender and APOE epsilon4 allele resulted in a global p value of 0.56.

Cognitive impairment and the role of the ApoE ε4‐allele after stroke—a 13 months follow‐up study

To examine the relationship between the ApoE epsilon4 allele and cognitive impairment 13 months after stroke. One hundred four stroke rehabilitation patients were cognitively tested on average 18 days after hospital admission and again 13 months later with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The following potential risk factors for post-stroke cognitive impairment (defined by a RBANS total index score below 77.5 points) at 13 months follow-up were analyzed in bivariate and logistic regression analyses: ApoE-genotype, socio-demographic variables, pre-stroke cognitive reduction (The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)), vascular factors, lesion characteristics, and neurological impairment (The National Institute of Health Stroke Scale (NIHSS)). Differences in general cognitive performance (pre-stroke, baseline, and follow-up) across patients with different ApoE-genotypes were analyzed, and lastly differences between epsilon4-carriers and non-carriers for changes in performance in various cognitive domains over the 13 months period were examined. Significant risk factors for cognitive impairment at 13 months were ApoE epsilon4, pre-stroke cognitive reduction (IQCODE 3.44+), previous stroke, and neurological impairment (NIHSS Total Score >5). A significant dose-dependent effect of the ApoE-genotype in relation to overall post-stroke cognitive functioning was found at baseline and follow-up, but not pre-stroke. The epsilon4 carriers showed a significant decline in tests related to verbal learning and memory compared to the non-carriers. The ApoE epsilon4-allele constitutes an independent risk factor for cognitive impairment at 13 months post-stroke, and is associated with progression of cognitive decline in tasks related to verbal learning and memory.

APOE ε4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors

Host genetic factors are important determinants for risk of HIV-1 infection and disease progression. This study examined associations of host genetic variants and neurocognitive impairment in Chinese individuals infected through contaminated blood products. Two hundred and one HIV-infected patients from Anhui, China, had neuropsychological tests at baseline and 12 months. DNA was genotyped for APOE epsilon2, epsilon3 and epsilon4 alleles; MBL2-A/O; CCR5-wt/Delta32; CCR5-59029-G/A; CCR2-180-G/A; SDF-1-G/A; IL4-589-C/T; MCP-1-2518-A/G; CX3CR1-745-G/A; -849-C/T polymorphisms and CCL3L1 copy number variants using real-time PCR. Univariate and multivariate analyses were performed. The cohort included 61% men, with mean education 5.5 years, AIDS diagnosis 113 (55%), on antiretrovirals 114 (56%), mean baseline CD4(+) cell count 349 cells/microl and mean log10 RNA 4.09. At baseline, 37% had global neuropsychological impairment increasing to 44% after 12 months. Of 43 patients with the APOE epsilon4 allele, 58% were cognitively impaired compared with 31% without the epsilon4 allele (P = 0.001, odds ratio 3.09, 95% confidence interval 1.54-6.18). The mean global deficit score (GDS) for epsilon4-positive participants on antiretrovirals for 12 months was 0.88 (0.55) compared with 0.63 (0.54) for epsilon4-negative participants (P = 0.053, 95% confidence interval -0.004 to 0.51). For MBL2, 52% of patients with the O/O genotype declined in cognitive function over 12 months compared with 23% with A/A (odds ratio 3.62, 95% confidence interval 1.46-9.03, P = 0.004). No associations were observed for the other genetic variants. The APOE epsilon4 allele was associated with increased risk for cognitive deficits, whereas the MBL2 O/O genotype was associated with increased risk for progressive cognitive decline in Chinese individuals infected with HIV through contaminated blood products.

Exploring Alzheimer's Disease in Zebrafish

The amyloid-beta protein (Abeta)-containing neuritic plaques and hyperphosphorylated tau-containing neurofibrillary tangles are two invariable characteristics of Alzheimer's disease (AD). Three genes encoding amyloid-beta protein precursor (AbetaPP), presenilin (PS) 1 and 2 are linked to early onset familial AD, and the apolipoprotein E (ApoE) epsilon4 allele is a major risk factor for sporadic AD. The zebrafish AbetaPP, PS, and ApoE genes have been identified, and the essential components of the gamma-secretase complex that mediates cleavage of AbetaPP to generate Abeta have been examined in zebrafish. A transgenic zebrafish expressing mutant tau has been created, and the transgenic animals exhibit a neurodegeneration phenotype. The use of zebrafish as a model system for AD research has expanded our knowledge of Abeta and tau.

Genetics of dementia

Dementia is a syndrome and not a single disease. Approximately 0.5% of those with Alzheimer's disease have an autosomal dominant inherited early onset Alzheimer's disease, caused by mutations in the APP, PSEN1 or PSEN2 gene. A large population-based twin study of late onset Alzheimer's disease supports complex inheritance. The APOE epsilon4 allele is a major risk factor for late onset Alzheimer's disease, whereas the epsilon2 allele has a protective effect. Two large size genome-wide association studies from two Internationals study groups recently identified the genes CLU, PICALM and CRI to be important for late onset Alzheimer's disease. Stroke is like dementia a syndrome and not a single disease. CADASIL is the most common autosomal dominant inherited cause of stroke and vascular dementia. CADASIL is caused by mutations in the NOTCH3 gene, which encodes a single-pass transmembrane receptor. Stroke can cause dementia, as it is the stroke itself rather than the underlying vascular risk factors that cause the dementia.

APOE ε4 and the cognitive genetics of multiple sclerosis

Evidence linking APOE to myelin repair, neuronal plasticity, and cerebral inflammatory processes suggests that it may be relevant in multiple sclerosis (MS). The purpose of this study was to determine whether the epsilon4 allele of APOE is associated with cognitive deficits in patients with MS. Using a case-control design, 50 patients with MS with the epsilon4 allele (epsilon4+) and 50 epsilon4-negative (epsilon4-) patients with MS were tested using a comprehensive battery of tests evaluating the cognitive domains most often affected in MS. The epsilon4+ and epsilon4- patients with MS were well-matched with respect to demographic variables (age, gender, ethnicity, education, employment status, premorbid IQ) and disease variables (disease course, disease duration, Expanded Disability Status Scale, 25-foot timed walk, 9-hole pegboard test). In addition, the groups were similar in depressive symptoms, in the proportion of patients receiving disease-modifying therapy, and in carriage of the APOE epsilon2 allele. Results showed that none of the 11 cognitive outcome variables differed between epsilon4+ and epsilon4- patients with MS. Cognitive measures were also unrelated to epsilon4 interactions with age and gender. The incidence of overall cognitive dysfunction did not differ between epsilon4+ and epsilon4- groups, nor did failure on any test, and epsilon4 carriage was not a significant predictor of any adverse cognitive outcome. These negative results endured with the exclusion of epsilon2+ subjects from the analyses. This study does not support a role for the epsilon4 allele in cognitive dysfunction in multiple sclerosis.

Effect of ApoE ε4 Allele on Visual Evoked Potentials and Resultant Flow Coupling in Patients With Alzheimer

The apolipoprotein E epsilon4 (ApoE epsilon4) allele is a strong susceptibility factor for Alzheimer disease, which promotes neurodegeneration and cerebrovascular dysfunction. To address this issue in more detail, we simultaneously obtained visual evoked potentials and resultant hemodynamic responses in newly diagnosed Alzheimer patients without signs of vascular lesions on a cerebral magnetic resonance imaging (MRI) scan. Patients were grouped according to ApoE genotype (n = 19 ApoE epsilon4 carrier and n = 12 noncarrier). ApoE epsilon4 carrier had significantly longer peak latencies and a trend to higher interpeak latencies of late potential components. Potential amplitudes and hemodynamic responses were similar in both groups. At the incidental stage of disease process, it appears that the ApoE epsilon4 allele mainly promotes neuronal dysfunction rather than aggravates neurovascular dysfunction. Studies with larger patient samples are warranted to corroborate the first findings.

Additive effects of LPL, APOA5 and APOEvariant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

BackgroundHypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information.MethodsA subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption.ResultsWe found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-ε4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG.ConclusionOur results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the ε4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.