Aims: The aim of the study was to determine whether the trajectory of learning and memory is modified according to an interaction between midlife or late life alcohol consumption status and the presence of one or more APOE e4 alleles. Methods: This was a secondary analysis of cognitive, genetic and alcohol consumption data collected from members of the Framingham Heart Study Offspring Cohort. Results: Light and moderate alcohol consumption during late life was associated with greater decline in learning and memory among APOE e4 carriers, whereas light and moderate alcohol consumption was associated with an increase in learning and memory among non-APOE e4 carriers. There was not a significant interaction between midlife alcohol consumption status and APOE e4 on the trajectory of learning and memory. Conclusion: Light to moderate alcohol consumption during late life may protect against a decline in learning and memory for non-APOE e4 allele carriers, but not for older adults who carry one or more APOE e4 alleles. 65 years of age or older upon receiving a baseline neuropsychological battery. Of the 2045 participants who received a baseline neuropsychological battery, 610 (29.8%) were 65

associated was hypertension, which was higher in group C. p¼ 0.002 OR 3,6 IC 95% 1,64-8,3 p ¼ 0.002 OR 3.6 95% CI 1.64 to 8.3. Conclusions: Our results show that aging is associated with a higher frequency in amnestic MCI component linked to a higher rate of conversion to dementia mainly mixed with a vascular component and influenced by hypertension.

Aims: The aim of the study was to determine whether the trajectory of learning and memory is modified according to an interaction between midlife or late life alcohol consumption status and the presence of one or more APOE e4 alleles. Methods: This was a secondary analysis of cognitive, genetic and alcohol consumption data collected from members of the Framingham Heart Study Offspring Cohort. Results: Light and moderate alcohol consumption during late life was associated with greater decline in learning and memory among APOE e4 carriers, whereas light and moderate alcohol consumption was associated with an increase in learning and memory among non-APOE e4 carriers. There was not a significant interaction between midlife alcohol consumption status and APOE e4 on the trajectory of learning and memory. Conclusion: Light to moderate alcohol consumption during late life may protect against a decline in learning and memory for non-APOE e4 allele carriers, but not for older adults who carry one or more APOE e4 alleles.

We propose a method for testing gene-environment (G × E) interactions on a complex trait in familybased studies in which a phenotypic ascertainment criterion has been imposed. This novel approach employs G-estimation, a semiparametric estimation technique from the causal inference literature, to avoid modeling of the association between the environmental exposure and the phenotype, to gain robustness against unmeasured confounding due to population substructure, and to acknowledge the ascertainment conditions. The proposed test allows for incomplete parental genotypes. It is compared by simulation studies to an analogous conditional likelihood-based approach and to the QBAT-I test, which also invokes the G-estimation principle but ignores ascertainment. We apply our approach to a study of chronic obstructive pulmonary disorder.

Background and objectives The serum proteins sclerostin and Dickkopf-1 (Dkk-1) are soluble inhibitors of canonical wnt signaling and were recently identified as components of parathyroid hormone (PTH) signal transduction. This study investigated the associations between sclerostin and Dkk-1 with histomorphometric parameters of bone turnover, mineralization, and volume in stage 5 chronic kidney disease patients on dialysis (CKD-5D).

Allele transmissions in pedigrees provide a natural way of evaluating the genotyping quality of a particular proband in a family-based, genome-wide association study. We propose a transmission test that is based on this feature and that can be used for quality control filtering of genome-wide genotype data for individual probands. The test has one degree of freedom and assesses the average genotyping error rate of the genotyped SNPs for a particular proband. As we show in simulation studies, the test is sufficiently powerful to identify probands with an unreliable genotyping quality that cannot be detected with standard quality control filters. This feature of the test is further exemplified by an application to the third release of the HapMap data. The test is ideally suited as the final layer of quality control filters in the cleaning process of genome-wide association studies. It identifies probands with insufficient genotyping quality that were not removed by standard quality control filtering.

Genome-wide association studies are identifying novel Alzheimer's disease (AD) risk factors. Elucidating the mechanism underlying these polymorphisms is critical to the validation process and, by identifying rate-limiting steps in AD risk, may yield novel therapeutic targets. Here, we elucidate the mechanism of action of the AD-associated polymorphism rs3865444 in the promoter of CD33, a member of the sialic acid-binding Ig-superfamily of lectins (SIGLECs). Immunostaining established that CD33 is expressed in microglia in human brain. Consistent with this finding, CD33 mRNA expression correlated well with expression of the microglial genes CD11b and AIF-1 and was modestly increased with AD status and the rs3865444C AD-risk allele. Analysis of CD33 isoforms identified a common isoform lacking exon 2 (D2-CD33). The proportion of CD33 expressed as D2-CD33 correlated robustly with rs3865444 genotype. Because rs3865444 is in the CD33 promoter region, we sought the functional polymorphism by sequencing CD33 from the promoter through exon 4. We identified a single polymorphism that is coinherited with rs3865444, i.e., rs12459419 in exon 2. Minigene RNA splicing studies in BV2 microglial cells established that rs12459419 is a functional single nucleotide polymorphism (SNP) that modulates exon 2 splicing efficiency. Thus, our primary findings are that CD33 is a microglial mRNA and that rs3865444 is a proxy SNP for rs12459419 that modulates CD33 exon 2 splicing. Exon 2 encodes the CD33 IgV domain that typically mediates sialic acid binding in SIGLEC family members. In summary, these results suggest a novel model wherein SNP-modulated RNA splicing modulates CD33 function and, thereby, AD risk.

Mild cognitive impairment (MCI) refers to the clinical state between normal cognition and probable Alzheimer's disease (AD), but persons diagnosed with MCI may progress to non-AD forms of dementia, remain MCI until death, or recover to normal cognition. Risk factors for these various clinical changes, which we term "transitions," may provide targets for therapeutic interventions. Therefore, it is useful to develop new approaches to assess risk factors for these transitions. Markov models have been used to investigate the transient nature of MCI represented by amnestic single-domain and mixed MCI states, where mixed MCI comprised all other MCI subtypes based on cognitive assessments. The purpose of this study is to expand this risk model by including a clinically determined MCI state as an outcome. Analyses show that several common risk factors play different roles in affecting transitions to MCI and dementia. Notably, APOE-4 increases the risk of transition to clinical MCI but does not affect the risk for a final transition to dementia, and baseline hypertension decreases the risk of transition to dementia from clinical MCI.

The minor allele of rs11136000 within CLU is strongly associated with reduced Alzheimer's disease (AD) risk. The mechanism underlying this association is unclear. Here, we report that CLU1 and CLU2 are the two primary CLU isoforms in human brain; CLU1 and CLU2 share exons 2-9 but differ in exon 1 and proximal promoters. The expression of both CLU1 and CLU2 was increased in individuals with significant AD neuropathology. However, only CLU1 was associated with the rs11136000 genotype, with the minor ''protective'' rs11136000T allele being associated with increased CLU1 expression. Since CLU1 and CLU2 are predicted to encode intracellular and secreted proteins, respectively, we compared their expression; for both CLU1 and CLU2 transfected cells, clusterin is present in the secretory pathway, accumulates in the extracellular media, and is similar in size to clusterin in human brain. Overall, we interpret these results as indicating that the AD-protective minor rs11136000T allele is associated with increased CLU1 expression. Since CLU1 and CLU2 appear to produce similar proteins and are increased in AD, the AD-protection afforded by the rs11136000T allele may reflect increased soluble clusterin throughout life.

This study utilized data from the Framingham Heart Study Offspring Cohort to examine the relationship between midlife and latelife alcohol consumption, cognitive functioning, and regional brain volumes among older adults without dementia or a history of abusing alcohol. The results from multiple linear regression models indicate that late life, but not midlife, alcohol consumption status is associated with episodic memory and hippocampal volume. Compared to late life abstainers, moderate consumers had larger hippocampal volume, and light consumers had higher episodic memory. The differences in episodic memory according to late life alcohol consumption status were no longer significant when hippocampal volume was included in the regression model. The findings from this study provide new evidence that hippocampal volume may contribute to the observed differences in episodic memory among older adults and late life alcohol consumption status.

Background: Previous research indicates that total cholesterol levels increase with age during young adulthood and middle age and decline with age later in life. This is attributed to changes in diet, body composition, medication use, physical activity, and hormone levels. In the current study we utilized data from the Framingham Heart Study Original Cohort to determine if variations in apolipoprotein E (APOE), a gene involved in regulating cholesterol homeostasis, influence trajectories of total cholesterol, HDL cholesterol, and total: HDL cholesterol ratio from midlife through late life. Methods: Cholesterol trajectories from midlife through late life were modeled using generalized additive mixed models and mixed-effects regression models. Results: APOE e2+ subjects had lower total cholesterol levels, higher HDL cholesterol levels, and lower total: HDL cholesterol ratios from midlife to late life compared to APOE e3 and APOE e4+ subjects. Statistically significant differences in life span cholesterol trajectories OPEN ACCESS Int. J. Environ. Res. Public Health 2014, 11 10664 according to gender and use of cholesterol-lowering medications were also detected. Conclusion: The findings from this research provide evidence that variations in APOE modify trajectories of serum cholesterol from midlife to late life. In order to efficiently modify cholesterol through the life span, it is important to take into account APOE allele status.