Variation In Apolipoprotein Research Articles

Chapter Five - Genetics of Alzheimer’s Disease

Alzheimer's disease (AD) represents the main form of dementia, and is a major public health problem. Despite intensive research efforts, current treatments have only marginal symptomatic benefits and there are no effective disease-modifying or preventive interventions. AD has a strong genetic component, so much research in AD has focused on identifying genetic causes and risk factors. This chapter will cover genetic discoveries in AD and their consequences in terms of improved knowledge regarding the disease and the identification of biomarkers and drug targets. First, we will discuss the study of the rare early-onset, autosomal dominant forms of AD that led to the discovery of mutations in three major genes, APP, PSEN1, and PSEN2. These discoveries have shaped our current understanding of the pathophysiology and natural history of AD as well as the development of therapeutic targets and the design of clinical trials. Then, we will explore linkage analysis and candidate gene approaches, which identified variants in Apolipoprotein E (APOE) as the major genetic risk factor for late-onset, "sporadic" forms of AD (LOAD), but failed to robustly identify other genetic risk factors, with the exception of variants in SORL1. The main focus of this chapter will be on recent genome-wide association studies that have successfully identified common genetic variations at over 20 loci associated with LOAD outside of the APOE locus. These loci are in or near-novel AD genes including BIN1, CR1, CLU, phosphatidylinositol-binding clathrin assembly protein (PICALM), CD33, EPHA1, MS4A4/MS4A6, ABCA7, CD2AP, SORL1, HLA-DRB5/DRB1, PTK2B, SLC24A4-RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, and TRIP4 and each has small effects on risk of AD (relative risks of 1.1-1.3). Finally, we will touch upon the ongoing effort to identify less frequent and rare variants through whole exome and whole genome sequencing. This effort has identified two novel genes, TREM2 and PLD3, and shown a role for APP in LOAD. The identification of these recently identified genes has implicated previously unsuspected biological pathways in the pathophysiology of AD.

The Pharmacogenetics of Cardiovascular Drugs / FARMAKOGENETIKA KARDIOVASKULARNIH LEKOVA

Summary This article will primarily summarize the current knowledge of the pharmacogenetics of commonly used drugs for the cardiovascular system: oral anticoagulants, antiplatelet therapy and statins. Coumarin anticoagulants are widely used to treat and prevent thromboembolisms. Variations in the CYP2C9 and VKORC1 genes influence the pharmacodynamic response to coumarins. Genetic variation makes an important contribution to the variation in the response to clopidogrel, the most commonly prescribed antiplatelet treatment. Genetic polymorphisms in the CYP2C19 gene as in the paraoxonase 1 gene are associated with clopidogrel effectiveness and have shown an association with excess of ischemic events such as myocardial infarction and stent thrombosis, but also with serious threat of bleeding. Statin pharmacogenetics has the potential to improve the safety and effectiveness of lipid-lowering therapy by statins. Genetic variations in apolipoprotein E, cholesterol ester transfer protein, kinesin-like protein 6, statin transporter OATP1B1 etc. could partly explain the interindividual variation in statins therapeutic response and adverse reactions. Finally, we comment on the pharmacogenetics of other cardiovascular drugs that have been extensively studied, but for which data are conflicting or that have not yet seen clinical implementation. Based on the available data, it could be expected that in the future genome-tailored drug prescription and use of defined algorithms will contribute to the successful drug action, lowering the frequency of adverse events, and will have greater clinical relevance.

Association between Apolipoprotein E Variants and Obesity-Related Traits in Mexican School Children

Background/Aim: Genetic variation in apolipoprotein E (ApoE) has a key role in lipid metabolism. However, its contribution to the amount and distribution of body fat is under investigation. The aim of this study was to analyze the association between genetic variation in ApoE and obesity-related traits in Mexican school children. Material and Methods: Anthropometric, body composition and physical activity measures were conducted using standard methods in 300 children (177 girls/123 boys) who fulfilled the inclusion criteria. DNA was isolated from saliva. ApoE genotypes were analyzed by allelic discrimination. The association between variation in ApoE and anthropometric and body composition measures was investigated using the General Linear Model. Results: The mean ± SD values for age, body mass index (BMI) and waist circumference (WC) were 9.05 ± 0.80 years, 19.01 ± 3.83 and 67.98 ± 10.97 cm, respectively. Approximately 46% of the participants were overweight or obese. A significant association between ApoE isoforms and WC was found after controlling for age, sex and the percentage of physical activity (p = 0.025). Significant main effects were found for vigorous physical activity and light physical activity influencing the adiposity-related BMI (p < 0.001) and WC (p = 0.044), respectively. Conclusions: Variation in ApoE and physical activity intensity were associated with adiposity-related phenotypes in Mexican school children.

Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation

Lipoprotein glomerulopathy is a rare inherited renal disease, caused by mutation of the APOE gene, characterized by proteinuria and nephrotic syndrome with elevated serum apoE. Since its treatment and outcome are unknown, we retrospectively studied 35 patients within 31 unrelated Han families with biopsy-proven lipoprotein glomerulopathy residing in the same county in southwest China. DNA sequencing detected the APOE Kyoto mutation (p. Arg25Cys) in all patients and 28 asymptomatic relatives. All shared the same ɛ3 allele. The patients presented with proteinuria, higher total triglyceride, and serum apoE levels relative to non-carriers. The serum apoE and triglyceride levels of asymptomatic carriers were between those of the patients and non-carriers. Sixteen patients received fenofibrate treatment for over 12 months. Six reached complete remission (proteinuria under 0.3 g/day with stable serum creatinine) with intensive control of their lipid profile (normalized serum apoE and triglycerides under 100 mg/dl). Eight reached partial remission. At 3 years of follow-up, patients treated with fenofibrate had superior survival and stable renal function. Thus, fenofibrate can induce lipoprotein glomerulopathy remission and the fibrate effects depend on the degree of lipid control and baseline proteinuria. Moreover, normalization of serum apoE and triglycerides can be used to judge the efficacy of lipid-lowering treatment.

Lack of association between apolipoprotein E genotypes and cognitive performance in the non‐demented elderly

The ε4 alelle of the apolipoprotein E gene is known to be a key genetic risk factor for Alzheimer's disease and possibly for other neurological disorders. Some evidence in the literature indicates that the ε4 allele interferes with human cognition independently of chronological age and diagnosis of Alzheimer's disease. The present study investigated the correlation of allelic variants of apolipoprotein E with the cognitive performance of elderly individuals without apparent cognitive impairment. This was a cross-sectional analysis that included 213 non-demented elderly individuals (age ≥60 years) from the Brazilian Federal District. The analysis assessed the subjects for cognitive domains including short- and long-term episodic memory, processing speed, and attention and executive functions. Sociodemographic and other clinical characteristics were gathered and analyzed as covariates. Being sufficiently powered, the present study did not identify differential performance across apolipoprotein E genotypes. There was no influence of age, gender, marital status, schooling, depressive symptoms or use of central nervous system depressants when the analyses were controlled for such factors. Our findings suggest that the ε4 allele does not contribute to detectable cognitive decline within the context of non-dementia.

Review article What causes alzheimer’s disease?

Since the earliest descriptions of Alzheimer's disease (AD), many theories have been advanced as to its cause. These include: (1) exacerbation of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3) an environmental factor such as exposure to aluminium, head injury, or malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes and allelic variation in apolipoprotein E (Apo E), (5) mitochondrial dysfunction, (6) a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these theories and concludes that AD is a multifactorial disorder in which genetic and environmental risk factors interact to increase the rate of normal aging ('allostatic load'). The consequent degeneration of neurons and blood vessels results in the formation of abnormally aggregated 'reactive' proteins such as β-amyloid (Aβ) and tau. Gene mutations influence the outcome of age-related neuronal degeneration to cause early onset familial AD (EO-FAD). Where gene mutations are absent and a combination of risk factors present, Aβ and tau only slowly accumulate not overwhelming cellular protection systems until later in life causing late-onset sporadic AD (LO-SAD). Aβ and tau spread through the brain via cell to cell transfer along anatomical pathways, variation in the pathways of spread leading to the disease heterogeneity characteristic of AD.

Impact of Genetic Variants of Apolipoprotein E on Lipid Profile in Patients with Parkinson's Disease

The pathogenesis of Parkinson's disease (PD) seems to involve genetic susceptibility to neurodegeneration. APOE gene has been considered a risk factor for PD. This study aimed to evaluate the association of APOE polymorphism with PD and its influence on lipid profile. We studied 232 PD patients (PD) and 169 individuals without the disease. The studied polymorphism was analyzed by PCR/RFLP. The Fisher's exact test, chi-square, ANOVA, and t-test (P < 0.05) were applied. The APOE3/3 genotype was prevalent in PD patients and Controls (P = 0.713) followed by APOE3/4 (P = 0.772). Both groups showed recommended values for lipid profile, with increase in the values of total cholesterol and LDLc, as well as decreased values of triglycerides in PD patients compared with Controls (P < 0.05 for all of them). Increased levels of HDLc, in PD patients, were associated with the APOE3/3 versus APOE-/4 genotypes (P = 0.012). The APOE polymorphism does not distinguish PD patients from Controls, as opposed to the lipid profile alone or in association with APOE. Furthermore, a relationship between increase of HDLc levels and APOE3 in homozygous was found in PD patients only.

Longitudinal Analysis of Maternal Plasma Apolipoproteins in Pregnancy: A Targeted Proteomics Approach

Minimally invasive diagnostic tests are needed in obstetrics to identify women at risk for complications during delivery. The apolipoproteins fluctuate in complexity and abundance in maternal plasma during pregnancy and could be incorporated into a blood test to evaluate this risk. The objective of this study was to examine the relative plasma concentrations of apolipoproteins and their biochemically modified subtypes (i.e. proteolytically processed, sialylated, cysteinylated, dimerized) over gestational time using a targeted mass spectrometry approach. Relative abundance of modified and unmodified apolipoproteins A-I, A-II, C-I, C-II, and C-III was determined by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry in plasma prospectively collected from 11 gravidas with uncomplicated pregnancies at 4-5 gestational time points per patient. Apolipoproteins were readily identifiable by spectral pattern. Apo C-III(2) and Apo C-III(1) (doubly and singly sialylated Apo C-III subtypes) increased with gestational age (r(2)>0.8). Unmodified Apo A-II, Apo C-I, and Apo C-III(0) showed no correlation (r(2) = 0.01-0.1). Pro-Apo C-II did not increase significantly until third trimester (140 ± 13% of first trimester), but proteolytically cleaved, mature Apo C-II increased in late pregnancy (702 ± 130% of first trimester). Mature Apo C-II represented 6.7 ± 0.9% of total Apo C-II in early gestation and increased to 33 ± 4.5% in third trimester. A label-free, semiquantitative targeted proteomics approach was developed using LTQ-Orbitrap mass spectrometry to confirm the relative quantitative differences observed by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry in Apo C-III and Apo C-II isoforms between first and third trimesters. Targeted apolipoprotein screening was applied to a cohort of term and preterm patients. Modified Apo A-II isoforms were significantly elevated in plasma from mothers who delivered prematurely relative to term controls (p = 0.02). These results support a role for targeted proteomics profiling approaches in monitoring healthy pregnancies and assessing risk of adverse obstetric outcomes.

To Know or Not to Know: An Update of the Literature on the Psychological and Behavioral Impact of Genetic Testing for Alzheimer Disease Risk

Alzheimer disease (AD) is a genetically heterogenous disorder; in rare cases autosomal dominantly inherited mutations typically cause early-onset familial AD (EOAD), whereas the risk for late-onset AD (LOAD) is generally modulated by genetic variants with relatively low penetrance but high prevalence, with variants in apolipoprotein E (APOE) being a firmly established risk factor. This article presents an overview of the current literature on the psychological and behavioral impact of genetic testing for AD. The few studies available for presymptomatic testing for EOAD showed that only a very small proportion of individuals had poor psychological outcomes as a result. Initial interest in testing for EOAD decreases significantly after identification of a specific mutation in a kindred, suggesting that interest and potential for knowledge may not translate into actual testing uptake. The majority of individuals from both the general population and those with a family history of AD had positive attitudes towards, and were interested in, susceptibility testing for APOE. Motivations for genetic testing included to provide information for future planning and to learn about one's own and one's children's risks of developing AD. Although susceptibility testing for APOE genotype is not currently recommended due to the lack of clinical utility, this review demonstrates that there is interest in testing and no obvious adverse psychological effects to those who have been tested.

Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase

Little is known about quality control of proteins that aberrantly or persistently engage the endoplasmic reticulum (ER)-localized translocon en route to membrane localization or the secretory pathway. Hrd1 and Doa10, the primary ubiquitin ligases that function in ER-associated degradation (ERAD) in yeast, target distinct subsets of misfolded or otherwise abnormal proteins based primarily on degradation signal (degron) location. We report the surprising observation that fusing Deg1, a cytoplasmic degron normally recognized by Doa10, to the Sec62 membrane protein rendered the protein a Hrd1 substrate. Hrd1-dependent degradation occurred when Deg1-Sec62 aberrantly engaged the Sec61 translocon channel and underwent topological rearrangement. Mutations that prevent translocon engagement caused a reversion to Doa10-dependent degradation. Similarly, a variant of apolipoprotein B, a protein known to be cotranslocationally targeted for proteasomal degradation, was also a Hrd1 substrate. Hrd1 therefore likely plays a general role in targeting proteins that persistently associate with and potentially obstruct the translocon.

The fibrillogenic L178H variant of apolipoprotein A-I forms helical fibrils

A number of amyloidogenic variants of apoA-I have been discovered but most have not been analyzed. Previously, we showed that the G26R mutation of apoA-I leads to increased β-strand structure, increased N-terminal protease susceptibility, and increased fibril formation after several days of incubation. In vivo, this and other variants mutated in the N-terminal domain (residues 26 to ∼90) lead to renal and hepatic accumulation. In contrast, several mutations identified within residues 170 to 178 lead to cardiac, laryngeal, and cutaneous protein deposition. Here, we describe the structural changes in the fibrillogenic variant L178H. Like G26R, the initial structure of the protein exhibits altered tertiary conformation relative to wild-type protein along with decreased stability and an altered lipid binding profile. However, in contrast to G26R, L178H undergoes an increase in helical structure upon incubation at 37°C with a half time (t1/2) of about 12 days. Upon prolonged incubation, the L178H mutant forms fibrils of a diameter of 10 nm that ranges in length from 30 to 120 nm. These results show that apoA-I, known for its dynamic properties, has the ability to form multiple fibrillar conformations, which may play a role in the tissue-specific deposition of the individual variants.

Genetic influences on cognitive decline in Parkinson's disease

The role of genetic factors in cognitive decline associated with Parkinson's disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule-associated protein tau (MAPT), or catechol-O-methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The ε4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7-4.1) of more points per year; P < 0.001) in total score and an increased risk of a ≥ 10 point drop during the follow-up period (hazard ratio, 2.8; 95% CI: 1.4-5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow-up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE ε4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

Apolipoprotein A-I amyloidogenic variant L174S, expressed and isolated from stably transfected mammalian cells, is associated with fatty acids

Sixteen variants of apolipoprotein A-I (ApoA-I) are associated with hereditary systemic amyloidoses, characterized by amyloid deposition in peripheral organs of patients. As these are heterozygous for the amyloidogenic variants, their isolation from plasma is impracticable and recombinant expression systems are needed. Here we report the expression of recombinant ApoA-I amyloidogenic variant Leu174 with Ser (L174S) in stably transfected Chinese hamster ovary-K1 cells. ApoA-I variant L174S was found to be efficiently secreted in the culture medium, from which it was isolated following a one-step purification procedure. Mass spectrometry analyses allowed the qualitative and quantitative definition of the amyloidogenic variant lipid content, which was found to consist of two saturated and two monounsaturated fatty acids. Interestingly, the same lipid species were found to be associated with the wild-type ApoA-I, expressed and isolated using the same cell system, with lower values of the lipid to protein molar ratios with respect to the amyloidogenic variant. A possible role of fatty acids in trafficking and secretion of apolipoproteins may be hypothesized.

Investigation of Polymorphic Variants ofPPARDandAPOEGenes in Turkish Coronary Heart Disease Patients

The aim of this study was to determine the role of polymorphic variants of apolipoprotein E (APOE) and peroxisome proliferator-activated receptor delta (PPARD) genes in the development of coronary heart disease (CHD), and the PPARD and APOE gene-gene interaction in a Turkish population. This study was carried out using a sample of 223 patients with CHD (103 with diabetes and 120 without diabetes) and 101 controls. PPARD +294T/C and APOE genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism technique. The PPARD and APOE genotype distributions were the same between study groups (p>0.05). In the nondiabetic CHD patients, the PPARD +294 C allele showed higher serum low-density lipoprotein cholesterol (LDL-C) level than the common +294 TT homozygote genotype (3.83 ± 1.01 vs. 3.33 ± 1.14, p=0.015). In addition, a significant association between APOE 4 and PPARD +294 C alleles was detected based on their effects on LDL-C in the nondiabetic CHD patients (+294 C/APOE4: 4.43 ± 0.88 vs. +294 TT/nonAPOE 4: 3.48 ± 1.09, p = 0.009). This association indicated the interaction of two genes on plasma LDL-C levels ascended in the order +294 T<+294 T-APOE 4<+294 C<APOE 4<+294 C-APOE 4. The PPARD +294 C allele was associated with higher incidence of left ventricular hypertrophy (LVH) in all male patients with body mass index >27. In addition, the CHD patients who were +294 C allele carriers had a 2.48-fold higher risk of LVH than subjects homozygous for the T allele. An increasing effect of the PPARD +294 C allele was shown on serum LDL-C levels in nondiabetic CHD patients. In addition, the results suggested that the +294 C allele might be associated with an increased LVH risk especially in male CHD patients. Furthermore, gene-gene interaction between the PPARD +294T/C and the APOE polymorphisms was observed regarding LDL-C concentrations.

Dementia, Stroke, and Vascular Risk Factors; a Review

Interest in dementia has increased over the past few decades. Stroke is an important cause of cognitive problems. The term vascular cognitive impairment is now used to describe dementia attributed to stroke or deep white matter lesions detected on imaging. Although vascular cognitive impairment is increasingly diagnosed, Alzheimer's disease remains the most common dementia worldwide. The relationship between Alzheimer's disease and vascular cognitive impairment is unclear, although there exists significant overlap, which prompts physicians to consider them opposite ends of a disease spectrum, rather than separate entities. There is also substantial evidence that stroke risk factors such as hypertension, diabetes; lipid disorders, etc. are independently associated with an increased risk of Alzheimer's disease and vascular cognitive impairment. Evidence suggests that these risk factors have a cumulative effect on Alzheimer's disease development but not on vascular cognitive impairment. This is more marked in Alzheimer's disease patients in the presence of the ε4 allelic variant of apolipoprotein E. How these risk factors increase the risk of dementia is largely unknown. Physicians must be aware that stroke causes dementia; that vascular risk factors appear to be independent risk factors in developing dementia, and that poststroke care must include cognitive assessment.

110 ASSOCIATIONS OF APOE POLYMORPHISMS WITH BASELINE LIPIDS AND RESPONSE TO ROSUVASTATIN VARY IN CHINESE PATIENTS WITH AND WITHOUT FAMILIAL HYPERCHOLESTEROLAEMIA

The aim was to evaluate the relationships of the T-1131C (rs662799) polymorphism variants of apolipoprotein A5 (Apo A5) gene and variants of apolipoprotein E (Apo E) gene common polymorphism (rs429358, rs7412) to signs of metabolic syndrome (MetS).We examined 590 asymptomatic dyslipidemic patients divided into MetS + (n = 146) and MetS − (n = 444) groups according to criteria of NCEP ATPIII Panel. We evaluated genotype frequencies and differences in MetS features between individual groups. Logistic regression analysis was used for the evaluation of Apo A5/Apo E variants as possible risk factors for MetS.We found no statistical differences between genotype and allele frequencies for both Apo A5 and Apo E polymorphisms between MetS + and MetS − groups. In all subjects and MetS − group, we confirmed well-known association of the − 1131C Apo A5 minor allele with elevated triglycerides (TG, p < 0.001). The Apo E gene E2 and E4 variants were associated with higher levels of TG (p < 0.01) in comparison to E33 common variant. However, no statistical differences were observed in MetS + subjects, regardless of significantly higher TG levels in this group. Apo A5/Apo E variant analysis in all dyslipidemic patients revealed significant increase of TG levels in all subgroups in comparison to common − 1131T/E3 variant carriers, the most in − 1131C/E4 variant subgroup. Logistic regression analysis models showed no association of Apo A5, Apo E and all Apo A5/Apo E variants with metabolic syndrome, even after adjustment for age and sex.Our study refined the role of Apo A5 and Apo E genetic variants in the group of adult dyslipidemic patients. We demonstrate that except of TG, Apo A5 T-1131C (rs662799) and Apo E (rs429358, rs7412) polymorphisms have no remarkable effect on MetS characteristics.

Alzheimer Disease: Advances in Pathogenesis, Diagnosis, and Therapy

Alzheimer disease (AD)9, the most frequent cause of dementia in Western societies, affects approximately 5.5 million people in the US and more than 35 million people worldwide. Common symptoms of this disease include memory loss, confusion, irritability, and aggression. Normal bodily functions are progressively lost, with AD becoming fatal within 3 to 9 years after diagnosis. The major risk factor for AD is advanced age. After the age of 65 years, the incidence of AD doubles every 5 years. As the size of the elderly population increases, particularly the “baby boomers,” the prevalence will approach 30 to 60 million cases in the US alone by 2050. The pathogenesis of AD is not clear, but the major pathogenetic mechanisms that have been suggested include the accumulation of misfolded proteins in the aging brain, which causes oxidative and inflammatory damage, which in turn leads to energy failure and synaptic dysfunction. A very small proportion (<1%) of AD cases are familial with early onset, and such cases have been linked to mutations in genes encoding amyloid precursor protein (APP) and presenilins 1 and 2. There is also a strong genetic association between one variant of apolipoprotein E (apo E) and the risk for developing AD. Over the last 10 years, there has been increased interest in understanding the pathogenesis of this disease and in the development of new therapies. We interview 4 specialists and examine the latest advances in pathogenesis, diagnosis, and therapy for this debilitating disease. Can you summarize briefly some new insights into the pathogenesis of AD? JoAnne McLaurin: We have understood for years that the biggest risk factor for AD is aging. We are now starting to unravel the effects of aging on memory function and link this back to disease progression. New data have arisen that link …

Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people.

Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ(2) for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ(2) for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.

Gonadal steroids do not affect apolipoprotein E expression in aging mouse cerebral cortex.

The allelic variant of apolipoprotein (Apo) E4 is a known risk factor for the development of most common late onset form of Alzheimer's disease (AD). As aging is associated with reduced circulating level of gonadal steroid hormones, hormone replacement therapies have been used for the possible treatment of AD. Both estrogen and testosterone have beneficial effects on brain due to interaction with apoE, but the underlying mechanism is still not clear. In this article, we report the effects of gonadectomy and hormone supplementation on apoE protein level in male and female mouse cerebral cortex during normal aging. We could not get any effect of gonadectomy and estradiol or testosterone treatment in adult and old mice of either sex. This suggests that during normal aging apoE protein level is not affected due to steroid hormone withdrawal or supplementation in the mouse cerebral cortex.

Apolipoprotein B genetic variants modify the response to fenofibrate: a GOLDN study

Hypertriglyceridemia, defined as a triglyceride measurement > 150 mg/dl, occurs in up to 34% of adults. Fenofibrate is a commonly used drug to treat hypertriglyceridemia, but response to fenofibrate varies considerably among individuals. We sought to determine if genetic variation in apolipoprotein B (APOB), an essential core of triglyceride-rich lipoprotein formation, may account for some of the inter-individual differences observed in triglyceride (TG) response to fenofibrate treatment. Participants (N = 958) from the Genetics of Lipid Lowering Drugs and Diet Network study completed a three-week intervention with fenofibrate 160 mg/day. Associations of four APOB gene single nucleotide polymorphisms (SNP) (rs934197, rs693, rs676210, and rs1042031) were tested for association with the TG response to fenofibrate using a mixed growth curve model where the familial structure was modeled as a random effect and cardiovascular risk factors were included as covariates. Three of these four SNPs changed the amino acid sequence of APOB, and the fourth was in the promoter region. TG response to fenofibrate treatment was associated with one APOB SNP, rs676210 (Pro2739Leu), such that participants with the TT genotype of rs676210 had greater TG lowering than those with the CC genotype (additive model, P = 0.0017). We conclude the rs676210 variant may identify individuals who respond best to fenofibrate for TG reduction.