Apolipoprotein E gene is related to mortality only in normal weight individuals: The Rotterdam study

Objective To investigate the relationship between the apolipoprotein E (APOE) gene and the risk of mortality in normal weight, overweight and obese individuals. Methods and Results In a population-based study of 7,983 individuals aged 55 years and older, we compared the risks of all-cause and coronary heart disease (CHD) mortality by APOE genotype, both overall and in subgroups defined by body mass index (BMI). We found significant evidence for interaction between APOE and BMI in relation to total cholesterol (p = 0.04) and HDL cholesterol (p < 0.001). Overall, APOE*2 carriers showed a decreased risk of all-cause mortality. Analyses within BMI strata showed a beneficial effect of APOE*2 only in normal weight persons (adjusted hazard ratio (HR) 0.7[95% CI 0.5–0.9]). APOE*2 was not associated with a lower risk of all-cause mortality in overweight or obese persons. The effect of APOE*2 in normal weight individuals tended to be due to the risk of CHD mortality (adjusted HR 0.5 [95% CI 0.2–1.2]). Conclusion The APOE*2 allele confers a lower risk of all-cause mortality only to normal weight individuals

Reduced Physiological Complexity in Robust Elderly Adults with the APOE ε4 Allele

BACKGROUND:It is unclear whether the loss of physiological complexity during the aging process is due to genetic variations. The APOE gene has been studied extensively in regard to its relationship with aging-associated medical illness. We hypothesize that diminished physiological complexity, as measured by heart rate variability, is influenced by polymorphisms in the APOE allele among elderly individuals. METHODOLOGY/PRINCIPAL FINDINGS:A total of 102 robust, non-demented, elderly subjects with normal functions of daily activities participated in this study (97 males and 5 females, aged 79.2+/-4.4 years, range 72-92 years). Among these individuals, the following two APOE genotypes were represented: epsilon4 non-carriers (n = 87, 85.3%) and epsilon4 carriers (n = 15, 14.7%). Multi-scale entropy (MSE), an analysis used in quantifying complexity for nonlinear time series, was employed to analyze heart-rate dynamics. Reduced physiological complexity, as measured by MSE, was significantly associated with the presence of the APOE epsilon4 allele in healthy elderly subjects, as compared to APOE epsilon4 allele non-carriers (24.6+/-5.5 versus 28.9+/-5.2, F = 9.429, p = 0.003, respectively). CONCLUSIONS/SIGNIFICANCE:This finding suggests a role for the APOE gene in the diminished physiological complexity seen in elderly populations

Apolipoprotein E Genotype and Cardiovascular Diseases in the Elderly

The apolipoprotein E (APOE) genotype is a genetic risk factor for dementia, Alzheimer’s disease, and cardiovascular disease (CVD). It includes three alleles (e2, e3, e4) that are located on chromosome 19q3.2. The e3 allele is the most common and is more common in people of Northern European ancestry and less common in those of Asian ancestry. Those with at least one e4 allele are at increased risk for CVD outcomes. It is well established that the presence of an e4 allele is linked to higher low-density lipoprotein cholesterol levels, even at young ages. Even though most CVD occurs in older people, there are few studies of the effects of APOE on CVD in older people. This review addresses recent research on the links between APOE, CVD, and vascular mechanisms by which APOE may affect CVD in the elderly

Genotypes at the APOE and SCA2 loci do not predict the course of multiple sclerosis in patients of Portuguese origin

Prova tipográfica (In Press)Multiple sclerosis (MS) is a demyelinating disease that affects about one in 500 young Europeans. In order to test the previously proposed influence of the APOE and SCA2 loci on susceptibility to MS, we studied these loci in 243 Portuguese patients and 192 healthy controls and both parents of 92 patients. We did not detect any significant difference when APOE and SCA2 allele frequencies of cases and controls were compared, or when we compared cases with different forms of the disease. Disequilibrium of transmission was tested for both loci in the 92 trios, and we did not observe segregation distortion. To test the influence of the APOE o4 and SCA2 22 CAGs alleles on severity of disease, we compared age at onset and progression rate between groups with and without those alleles. We did not observe an association of the o4 or the 22 CAGs alleles with rate of progression in our total patient population; allele o4 was associated with increased rate of progression of MS in a subset of patients with less than 10 years of the disease. However, globally in the Portuguese population, the APOE and SCA2 genes do not seem to be useful in the clinical context as prognostic markers of this disorder.Fundação para a Ciência e a Tecnologia (FCT) - grant SFRH/BD/9111/2002.Serono Portugal

Multivariate Protein Signatures of Pre-Clinical Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Plasma Proteome Dataset

Background: Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD. Methods and Findings: We focused on identifying signatures that discriminate cognitively normal controls (n = 54) from individuals with MCI who subsequently progress to AD (n = 163). Based on p value, apolipoprotein E (APOE) showed the strongest difference between these groups (p = 2.3×10−13). We applied a multivariate approach based on combinatorial optimization ((α,β)-k Feature Set Selection), which retains information about individual participants and maintains the context of interrelationships between different analytes, to identify the optimal set of analytes (signature) to discriminate these two groups. We identified 11-analyte signatures achieving values of sensitivity and specificity between 65% and 86% for both MCI and AD groups, depending on whether APOE was included and other factors. Classification accuracy was improved by considering “meta-features,” representing the difference in relative abundance of two analytes, with an 8-meta-feature signature consistently achieving sensitivity and specificity both over 85%. Generating signatures based on longitudinal rather than cross-sectional data further improved classification accuracy, returning sensitivities and specificities of approximately 90%. Conclusions: Applying these novel analysis approaches to the powerful and well-characterized ADNI dataset has identified sets of plasma biomarkers for pre-clinical AD. While studies of independent test sets are required to validate the signatures, these analyses provide a starting point for developing a cost-effective and minimally invasive test capable of diagnosing AD in its pre-clinical stages