Influence Of APOE Genotype Research Articles

Effect of Genetic Risk on the Relationship Between rs-fMRI Complexity and Tau and Amyloid PET in Alzheimer's Disease.

Reduced functional magnetic resonance imaging (fMRI)-complexity in Alzheimer's disease (AD) progression has been demonstrated and found to be associated with tauopathy and cognition. However, association of fMRI-complexity with amyloid and influence of genetic risk (APOEɛ4) remain unknown. Here we investigate the association between fMRI-complexity, tau-PET, and amyloid-PET as well as influence of APOE genotype using multivariate generalized linear models. We show that fMRI-complexity has a strong association with tau but not amyloid deposition and that the presence of an APOEɛ4 allele enhances this effect. Thus fMRI-complexity provides a surrogate marker of impaired brain functionality in AD progression.

Repetitive head trauma and apoE4 induce chronic cerebrovascular alterations that impair tau elimination from the brain

Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The expression of the apolipoprotein E4 (apoE4) isoform has been associated with higher levels of tau in the brain, and worse clinical outcomes after r-mTBI, though the influence of apoE genotype on extracellular tau dynamics in the brain is poorly understood. We recently demonstrated that extracellular tau can be eliminated across blood-brain barrier (BBB), which is progressively impaired following r-mTBI. The current studies investigated the influence of repetitive mild TBI (r-mTBI) and apoE genotype on the elimination of extracellular solutes from the brain. Following intracortical injection of biotin-labeled tau into humanized apoE-Tr mice, the levels of exogenous tau residing in the brain of apoE4 mice were elevated compared to other isoforms, indicating reduced tau elimination. Additionally, we found exposure to r-mTBI increased tau residence in apoE2 mice, similar to our observations in E2FAD animals. Each of these findings may be the result of diminished tau efflux via LRP1 at the BBB, as LRP1 inhibition significantly reduced tau uptake in endothelial cells and decreased tau transit across an in vitro model of the BBB (basolateral-to-apical). Notably, we showed that injury and apoE status, (particularly apoE4) resulted in chronic alterations in BBB integrity, pericyte coverage, and AQP4 polarization. These aberrations coincided with an atypical reactive astrocytic gene signature indicative of diminished CSF-ISF exchange. Our work found that CSF movement was reduced in the chronic phase following r-mTBI (>18 months post injury) across all apoE genotypes. In summary, we show that apoE genotype strongly influences cerebrovascular homeostasis, which can lead to age-dependent deficiencies in the elimination of toxic proteins from the brain, like tau, particularly in the aftermath of head trauma.

Design and Rationale of a Two-Armed Randomized Controlled Trial on Yoga/Brisk Walking-Based Lifestyle Modification on Dementia Risk Reduction, and Influence of ApoE Genotypes on the Intervention.

Though considered a late-onset disease, the 2020 report of the Lancet Commission emphasizes the necessity of conducting primary prevention trials with an approach of never too early in the life course for dementia prevention. Driven by the same notion, we hereby aim to compare the dementia risk reduction potential of two potential interventions, 48 weeks (12 months) of yoga and brisk walking, in middle-aged high-risk subjects. A randomized controlled trial. Community in India. In total, 323 at-risk dementia subjects will be recruited from community settings through health awareness camps and door-to-door surveys across Delhi, India. Participants will be randomized into yoga or brisk-walking groups (1:1). The yoga intervention group will receive 60 contact yoga sessions per 60-min/day at the community parks, followed by continued tele-supervised home practice, further followed by at-home self-practice, and will be tested at 3-time points (baseline, 24-week and 48-week, post-randomization) to test the efficacy of the intervention. The control group will be asked to do brisk walking daily for 45 minutes at their convenience, followed by weekly telephone follow-ups. Applying the intention-to-treat principle, the primary endpoint will be the change from baseline at the 12th month in the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) Scores. Secondary outcomes will include the composite scores derived from a comprehensive neuropsychology battery, comprising the Trail Making Test, Digit Span Test, N Back, Color Trail, Animal Fluency Test, COWA (Controlled Oral Word Association Test), and Digit Symbol Substitution. The primary outcome will be analyzed using mixed-effect models for repeated measures, adjusted for covariates as fixed effects. The study has been prospectively registered (CTRI/2023/02/049746) on February 15, 2023. The protocol was conceptualized in 2021 and approved by the Institutional Ethics Committee of SVYASA. Recruitment began in February 2023 and is underway with patient enrollment. To our knowledge, this is the first controlled trial to investigate the longitudinal effects of a yoga-based intervention on dementia risk reduction using the CAIDE risk score. The findings of this trial will also provide insight into a better understanding of genotype-dependent responses to yoga intervention and open up avenues for understanding the implications of gene-intervention interactions for precision prevention using yoga.

ApoE4 expression disrupts tau uptake, trafficking, and clearance in astrocytes.

Tauopathies are a collection of neurodegenerative diseases characterized by the accumulation of pathogenic aggregates of the microtubule-associated protein tau. Despite the prevalence and diversity of tau astrogliopathy in tauopathies, the interactions between astrocytes and tau in the brain, and the influence of neurodegenerative genetic risk factors like the apolipoprotein E4 (apoE4) isoform, are largely unknown. Here, we leveraged primary and immortalized astrocytes expressing humanized apoE isoforms to characterize the mechanisms by which astrocytes interact with and eliminate extracellular tau, and the influence of apoE genotype on these processes. Our work indicates that astrocytes rapidly internalize, process, and release tau via an exosomal secretory mechanism under physiological conditions. However, we found that apoE4 disrupted these processes in comparison to apoE3, resulting in an astrocytic phenotype prone to intracellular tau accumulation. Furthermore, exposure to repetitive mild traumatic brain injuries exacerbated the apoE4-induced impairments in tau processing and elimination by astrocytes in apoE4 targeted-replacement mice. The diminished ability of apoE4 astrocytes to eliminate extracellular tau can lead to an accumulation of pathogenic tau, which induces mitochondrial dysfunction, as demonstrated by our studies. In total, our findings suggest that the apoE4 isoform lowers the threshold of astrocytic resilience to pathogenic tau, rendering them susceptible to bioenergetic deficits in the early stages of neurodegenerative diseases such as traumatic brain injury, potentially contributing to neurological decline.

Sex differences of APOE neuropathology‐based scores in brain aging

AbstractBackgroundBy reinterpreting the difference between a model prediction and calendar age, machine learning algorithms allow for estimation of “brain age” using MRI. There is growing evidence for sex differences in the influence of APOE genotype (evaluated as APOE ε4 carrier status) on Alzheimer’s disease (AD) endophenotypes at various stages of disease. The purpose of this study is to examine the influence of an APOE neuropathology‐based score (APOE npscore) on the brain aging estimated from deep learning.MethodsBrain age from 274 participants (Fig. 1) in the Wisconsin‐ADRC was estimated from T1w‐MRI using a publicly available deep learning model called two‐stage‐age‐network (TSAN) that was pre‐trained on over four thousand scans from OASIS, ADNI‐I and PAC‐2019. TSAN uses a novel rank‐based loss along with mean squared loss and makes predictions in two steps which does not require a posteriori bias correction. This is a significant improvement from prior deep learning models in reducing the “regression‐to‐mean bias” typically present in brain age models. APOE genotypes (ε2ε2, ε2ε3, ε3ε3, ε2ε4, ε3ε4, ε4ε4) were weighted by the log(odds‐ratio) from a large study of autopsy‐confirmed AD cases/controls, providing a variable representing the relative amount of risk across APOE genotypes. Mood’s median test was used to examine the sex differences between the excess brain aging (EBA) as a function of the APOE npscore.Results Fig. 2 shows the brain age predictions. Fig. 3 shows that there are significant differences between females and males in the EBA for the APOE npscore <0. Median EBA for both males and females is <0 when APOE npscore <0 suggesting protective effects of ε2 on brain aging. The median EBA >0 for both the sexes when APOE npscore ≥0.ConclusionWe report sex differences in the influence of APOE genotype on brain aging. There is heterogeneity in the differences within the ε4+ (APOE npscore >0) and ε4‐ (APOE npscore ≤0) groups. These sex differences may not be observed when using just ε4 carrier status instead of the APOE npscore. This provides evidence for a shift in paradigm for the way we analyze APOE genotype because of latent nuances of the ε4‐status influence on AD outcomes.

The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice.

The apolipoprotein E4 (APOE4) genotype is predictive of Alzheimer's disease (AD). The brain is highly enriched with the omega-3 polyunsaturated fatty acid (n3-PUFA), docosahexaenoic acid (DHA). DHA's metabolism is defective in APOE4 carriers. Flavanol intake can play a role in modulating DHA levels. However, the impact of flavanol co-supplementation with fish oil on brain DHA uptake, status and partitioning, and according to APOE genotype is currently unknown. Here, using a humanised APOE3 and APOE4 targeted replacement transgenic mouse model, the interactive influence of cocoa flavanols (FLAV) and APOE genotype on the blood and subcortical brain PUFA status following the supplementation of a high fat (HF) enriched with DHA from fish oil (FO) was investigated. DHA levels increased in the blood (p < 0.001) and brain (p = 0.001) following supplementation. Compared to APOE3, a higher red blood cell (RBC) DHA (p < 0.001) was evident in APOE4 mice following FO and FLAV supplementation. Although FO did not increase the percentage of brain DHA in APOE4, a 17.1% (p < 0.05) and 20.0% (p < 0.001) higher DHA level in the phosphatidylcholine (PC) fraction in the HF FO and HF FO FLAV groups, and a 14.5% (p < 0.05) higher DHA level in the phosphatidylethanolamine (PE) fraction in the HF FO FLAV group was evident in these animals relative to the HF controls. The addition of FLAV (+/- FO) did not significantly increase the percentage of brain DHA in the group as a whole. However, a higher brain: RBC DHA ratio was evident in APOE3 only (p < 0.05) for HF FLAV versus HF. In conclusion, our data shows only modest effects of FLAV on the brain DHA status, which is limited to APOE3.

Differentially methylated CpG sites between APOE ε4 carriers and non‐carriers in blood and brain from Alzheimer disease cases and controls

AbstractBackgroundThe APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer disease (AD). Methylation changes have been shown to occur early in AD, however, the influence of APOE genotype on methylation especially in relation to AD remains largely unknown.MethodWe evaluated differential methylation of genome‐wide CpG sites in brain between 178 APOE ε4 carriers and 511 ε4 non‐carriers in the Religious Orders Study and Memory and Aging Project (ROSMAP), in blood between 276 APOE ε4 carriers and 1118 ε4 non‐carriers in the Framingham Heart Study (FHS), and in blood between 114 APOE ε4 carriers and 187 ε4 non‐carriers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methylation patterns of the top‐ranked CpG sites were further examined in FHS participants with respect to cognitive and brain imaging traits.ResultThe most differentially methylated CpG sites among the autosomes were observed in the APOE region (chr19:45380000‐45430000) in all datasets. Significantly (P&lt;10‐8) hypomethylated CpG sites in APOE ε4 carriers compared to non‐carriers were observed from the APOC1 gene in the FHS (cg23270113, cg05644480) and ADNI (cg07773593) datasets (P=4.6x10‐9) and from the TOMM40 gene (cg02613937, P=1.3x10‐13) in the ROSMAP dataset. Significantly (P&lt;10‐8) hypermethylated CpG sites in APOE ε4 carriers compared to non‐carriers were observed from the APOE gene in the ROSMAP (cg14123992, cg04406254) and FHS (cg06750524) datasets. The two APOC1 CpG sites were significantly associated (P&lt;0.05) with amyloid‐beta 42 level in plasma and several cognitive tests (Trail A, Paired Associate Learning, Verbal Fluency Test, Boston Naming Test). APOE CpG site cg06750524 was significantly associated with MRI volumetric measures of the cerebrum (P=0.01), temporal cortex (P=0.02), and frontal cortex (P=0.05).ConclusionWe discovered novel CpG methylation differences in blood and brain between APOE ε4 carriers and non‐carriers that are associated with AD‐related traits especially involved in executive function and language. Further studies are required to link the methylation patterns to mechanisms leading to AD.

Influence of APOE Genotype on Mortality and Cognitive Impairment.

While many studies have examined the associations between APOE genotype and mortality, findings have often been conflicting and it remains unclear whether APOE genotype affects longevity. Using selected individuals from the Manchester arm of the Brains for Dementia Research programme and University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, we investigated relationships between APOE genotype and age at death in both cognitively normal and cognitively impaired individuals. Results indicated that carrying the APOE ɛ4 allele led to a reduced chance in an individual reaching 80+ years and remaining cognitively healthy. Conversely, APOE ɛ2 carriers tended to live longer and remain cognitively normal. These findings add to the evidence that APOE genotype influences longevity, especially in cognitively impaired individuals who carry the APOE ɛ4 allele.

Influence of ApoE Genotype and Clock T3111C Interaction with Cardiovascular Risk Factors on the Progression to Alzheimer's Disease in Subjective Cognitive Decline and Mild Cognitive Impairment Patients.

Background: Some genes could interact with cardiovascular risk factors in the development of Alzheimer’s disease. We aimed to evaluate the interaction between ApoE ε4 status, Clock T3111C and Per2 C111G polymorphisms with cardiovascular profile in Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI). Methods: We included 68 patients who underwent clinical evaluation; neuropsychological assessment; ApoE, Clock and Per2 genotyping at baseline; and neuropsychological follow-up every 12–24 months for a mean of 13 years. We considered subjects who developed AD and non-converters. Results: Clock T3111C was detected in 47% of cases, Per2 C111G in 19% of cases. ApoE ε4 carriers presented higher risk of heart disease; Clock C-carriers were more frequently smokers than non C-carriers. During the follow-up, 17 patients progressed to AD. Age at baseline, ApoE ε 4 and dyslipidemia increased the risk of conversion to AD. ApoE ε4 carriers with history of dyslipidemia showed higher risk to convert to AD compared to ApoE ε4− groups and ApoE ε4+ without dyslipidemia patients. Clock C-carriers with history of blood hypertension had a higher risk of conversion to AD. Conclusions: ApoE and Clock T3111C seem to interact with cardiovascular risk factors in SCD and MCI patients influencing the progression to AD.

Association of Apolipoprotein E Gene Polymorphism with Lipid Profile in Patients with Acute Coronary Syndrome in Han Chinese: A Critical Review

This review paper focuses on the genetic contribution, in particular, the association of Apolipoprotein E gene polymorphism to lipid abnormality and subsequent acute coronary syndrome in Han Chinese of China. Many researches have been published pertaining the influence of ApoE gene polymorphism on coronary artery disease, dyslipidemia and the response of statin in Han Chinese. Most of the studies in Han Chinese like other populations demonstrated that ApoE 4 allele genetically predisposes coronary artery disease, acute coronary syndrome, severity of occlusion of coronary artery and higher incidence of major adverse cardiovascular events (In Han Chinese, ApoE allele carriers demonstrated 85% increase in major adverse cardiovascular events (MACE) in six months follow up). In addition, ApoE4 allele carrier also showed both increased in LDL level and decrease response to statin therapy in dyslipidemic Han Chinese. On the other hand, ApoE2 carrier is scavenger of cholesterol and triglyceride from the blood; thus it is cardiovascular-protective. Despite positive relationship between ApoE gene polymorphism and cardiovascular pathologies, prognostic outcome and resistance to intervention, this area of research still requires extensive investigation in Han Chinese. Because, several other studies revealed either negative effect or showed no effect by ApoE gene polymorphism on cardiovascular disease. Some of the causes of such debatable results could be explained by factors such as diminutive frequency allele and expression of ApoE gene in coronary heart disease. This part of the research yet requires extensive study with bulkier sample size and retrospective in nature, in order to ascertain the influence of ApoE genotype on lipid, anti-hyperlipidemic agent and coronary heart disease. Such studies could assist us to confirm whether to test healthier subjects to predict genetic risk of coronary heart disease in Han Chinese population. The aim of this review paper is to critically analyze the effect of ApoE gene on the occurrence of coronary heart disease in Han Chinese.

Putting attention in the spotlight: The influence of APOE genotype on visual search in mid adulthood

The Apolipoprotein E e4 allele is associated with greater cognitive decline with age, yet effects of this gene are also observed earlier in the lifespan. This research explores genotype differences (e2, e3, e4) in the allocation of visuospatial attention in mid-adulthood. Sixty-six volunteers, aged 45–55 years, completed two paradigms probing the active selection of information at the focus of attention (a dynamic scaling task) and perceptual capacity differences. Two methods of statistical comparison (parametric statistics, Bayesian inference) found no significant difference between e4 carriers and the homozygous e3 group on either the dynamic scaling or perceptual load task. E2 carriers, however, demonstrated less efficient visual search performance on the dynamic scaling task. The lack of an e4 difference in visuospatial attention, despite previous suggestion in the literature of genotype effects, indicates that select attentional processes are intact in e4 carriers in mid-adulthood. The association of e2 genotype with slower visual search performance complicates the premised protective effects of this allele in cognitive ageing.

MicroRNAs in Human Cerebrospinal Fluid as Biomarkers for Alzheimer's Disease.

Currently available biomarkers of Alzheimer's disease (AD) include cerebrospinal fluid (CSF) protein analysis and amyloid PET imaging, each of which has limitations. The discovery of extracellular microRNAs (miRNAs) in CSF raises the possibility that miRNA may serve as novel biomarkers of AD. Investigate miRNAs in CSF obtained from living donors as biomarkers for AD. We profiled miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays. Replicate studies performed on a subset of 32 of the original CSF samples verified 20 high confidence miRNAs. Stringent data analysis using a four-step statistical selection process including log-rank and receiver operating characteristic (ROC) tests, followed by random forest tests, identified 16 additional miRNAs that discriminate AD from controls. Multimarker modeling evaluated linear combinations of these miRNAs via best-subsets logistic regression, and computed area under the ROC (AUC) curve ascertained classification performance. The influence of ApoE genotype on miRNA biomarker performance was also evaluated. We discovered 36 miRNAs that discriminate AD from control CSF. 20 of these retested in replicate studies verified differential expression between AD and controls. Stringent statistical analysis also identified these 20 miRNAs, and 16 additional miRNA candidates. Top-performing linear combinations of 3 and 4 miRNAs have AUC of 0.80-0.82. Addition of ApoE genotype to the model improved performance, i.e., AUC of 3 miRNA plus ApoE4 improves to 0.84. CSF miRNAs can discriminate AD from controls. Combining miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE genotype improves classification.

The influence of ApoE genotype on the lipid profile and lipoproteins during normal pregnancy in a Southern African population.

Pregnancy is associated with increases in fasting triglycerides and total cholesterol.1 ApoE isoforms are known to influence the concentration of cholesterol, with apoE2 homozygosity lowering and apoE4 homozygosity raising the cholesterol concentration compared with E3 homozygosity.2 The lipid profiles ApoE status and prevalence of small dense LDL species were evaluated for subjects attending an antenatal clinic. Samples from 690 women aged between 16 and 42 years of age were analyzed during and after pregnancy. The fasting plasma triglyceride concentration (in mmol/L) was significantly higher in pregnancy (median = 1.5, IQR 1.0-2.0 vs median = 0.6, IQR 0.5-0.8 respectively, p < 0.0001). Similarly, the total cholesterol (in mmol/L) was increased during pregnancy (median=4.1, IQR 3.6-4.7 vs median 3.5, IQR 3.1-3.5, respectively p=0.0167). The median LDL cholesterol and HDL cholesterol did not change. Higher proportions of small density LDL species were seen during pregnancy compared to after pregnancy. The distribution of the LDL species during pregnancy and 6 weeks post-partum were significantly different p<0.0001 with the smaller species being much higher during pregnancy. ApoE4 genotype was associated with increased total cholesterol and LDL cholesterol concentrations during pregnancy. Pregnancy results in a reversible remodeling of LDL to smaller species, the significance of which is unknown but may indicate a predisposition to atherosclerosis.

Abstract WP358: APOE Polymorphisms Influence Longitudinal Lipid Trends Preceding Primary Intracerebral Hemorrhage

Introduction: Primary intracerebral hemorrhage (ICH) remains one of the most severe forms of acute cerebrovascular disease. APOE ε2 and ε4 are risk factors for primary ICH, and also involved in regulation of circulating lipid levels. Hypercholesterolemia has been associated with reduced ICH risk. However, the biological mechanisms mediating the roles of APOE and serum lipids on ICH risk remain unclear. Given the pleiotropic relationship between APOE, ICH, and serum lipid levels, we sought to determine the influence of APOE genotype on temporal serum lipid trends before and after ICH. Methods: We performed a single-center retrospective longitudinal cohort analysis using subjects with known APOE genotype drawn from an ongoing cohort study of primary ICH. Serum lipid measurements for total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) collected within 2 years preceding and following index ICH were extracted from electronic medical records (EMR). Piecewise linear mixed-effects random-coefficent models were used to compare APOE allele-specific effects on changes in serum lipid trends in ICH. Results: 124 ICH cases were analyzed. APOE ε4 carriers had significantly greater rates of decline in serum TC and LDL levels within 6 months prior to ICH (TC: -7.30 mg/dL/month, p=0.0035; LDL: -8.44 mg/dL/month, p=0.0001) compared to non-carriers (TC: -3.79 mg/dL/month, p=0.17; LDL: -2.39 mg/dL/month, p=0.55). In contrast, TC and LDL trends for APOE ε2 carriers were not significantly altered within the same time period. APOE genotype had no associations with serum HDL or TG trends. Conclusions: APOE allele status is a strong predictor of subacute serum TC and LDL changes preceding ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. While further studies are needed, our observation that APOE ε4 influences serum lipid trends preceding ICH provides additional insight towards lipid-dependent and lipid-independent APOE-genotype specific effects on stroke risk and suggests that characterization of the metabolic role of APOE is needed to improve understanding of APOE biology in cerebrovascular disease.

Alzheimer's Disease and Cognitive Frailty: Novel Therapeutic Technologies.

Worldwide, 46.8 million people have dementia, and every year there are over 9.9 million new diagnosed cases [1], with an increase of the economic impact and cost of the 35.4% from 2010 [1]. Alzheimer's disease (AD) is the most common form of dementia [2] and represents one of the major causes of disability, dependency, burden, and stress of caregivers increasing institutionalization among older people worldwide [3]. A precursor of neurodegenerative processes may be represented by Cognitive Frailty (CF) that includes reversible and potentially reversible subtypes [4]. Risk factors for CF and AD appear to change with age. Most very elderly individuals have beta-amyloid (Aβ) plaques within their brains, indicating that AD pathology may be present in asymptomatic elders and that these individuals will ultimately develop clinical symptoms of AD if they live long enough. According to the preclinical AD criteria, therefore, it is difficult to see how brain amyloidosis and brain aging could be considered separate entities arising through independent mechanisms. In this special issue, investigators reported studies into the subject from all over the world (i.e., Switzerland, Germany, Egypt, China, Spain, Australia, Italy, Brazil, and USA). They contributed to increasing the knowledge on to individualize genetic and clinic mechanisms of AD and CF considering age-related and multidimensional approaches to the purpose of appropriate and personalized treatment. In a preclinical model, S. AbdAlla et al. subjected aged rats to chronic unpredictable mild stress, which is known to enhance the development of AD-related neuropathological features, and showed that four weeks of chronic mild stress induced a strong upregulation of the hippocampal angiotensin-converting enzyme (ACE), both at gene expression and at protein levels. The authors reported that ACE inhibition targets neurodegeneration triggered by environmental stress. C. Ma et al. started from the assumption that advancing age, chronic inflammation, oxidative damage, and disorders of lipid metabolism are positively linked to the late-life cognitive impairment. This study demonstrated that age, levels of fundus atherosclerosis, serum biomarkers peroxidase, interleukin-6, serum levels of high-density lipoprotein cholesterol, ApoA2, and ApoC2 were significantly related to cognitive status. Moreover, ApoA1 and ApoA2 were found to be possible risk factors of cognitive impairment and late-life dementia. J. A. Monge-Argiles et al. analyzed cerebrospinal fluid (CSF) biomarkers and tau/Aβ ratios in MCI patients and control subjects, using ELISA methodology. This study contributed to evaluation of the association between apolipoprotein E (ApoE) genotype and CSF levels of AD biomarkers and the influence of ApoE genotype on the development of AD in a Spanish population. G. Lyons et al. described the “Deep Assessment,” which is a novel multifaceted framework for delivering a more comprehensive and authentic assessment of the internal states of people with severe cognitive impairments who are unable to self-report. This paper suggested how Deep Assessment can be applied to people with advanced AD to develop others' understanding of their inner states and to help improve their quality of life. Moreover G. Lyons et al. discussed the potential utility and efficacy of this technique for this population and also proposed other human conditions that may benefit from research using a Deep Assessment approach. F. Panza et al. reviewed tau-centric targets and drugs in clinical development for the treatment of AD and reported that methylene blue seems to be an inhibitor of the tau protein aggregation. Finally, A. M. de Oliveira et al. reviewed studies of nonpharmacological interventions published in the last 10 years and reported that such approaches may help reduce behavioral and psychological symptoms of dementia (BPSD) such as agitation, psychotic symptoms, and apathy. This study highlighted the role of nonpharmacological interventions programs in the clinical management of BPSD, as an alternative to (or in combination with) conventional pharmacological treatments (e.g., antipsychotics and benzodiazepines) that may elicit undesired side effects. The pharmacologic treatments, even if they are supported by several studies, deliver limited symptomatic benefits, so the provision of nonpharmacological treatments in addition to standard outpatient care is an asset of good clinical practice. Therefore prognostic evaluation of AD patients plays a key role in the decision analyses of care processes including the organization of social health care system, the support to families, caregivers, and patients as well as the choice of appropriate treatment. Grazia D'Onofrio Zhuowei Yu Orestes V. Forlenza

Effect of atorvastatin and niacin/LRPT on apolipoprotein e distribution, metabolism and glycation

Aim: To investigate the influence of apoE genotype on the response to atorvastatin treatment in patients with Type 2 diabetes with nephropathy and the effect of niacin/laropiprant (LRPT) on apoE and glycated apoE concentration and distribution in hyperlipidaemia.Methods: ApoE genotype and the effect of 10mg/day and 80mg/day atorvastatin treatment on apoE concentration were studied in 85 patients with type 2 diabetes with nephropathy. The effect of niacin/LRPT on apoE and glycated apoE was investigated for 36 patients with hyperlipidaemia. Results: After 12 months treatment with atorvastatin, serum apoE concentration decreased significantly in the 80mg/day, but not the 10mg/day group. This decrease was observed in patients with E3 and E4 but not E2 genotype. Hyperlipidaemia did not affect total apoE, but the apoE distribution in HDL and d>1.21g/ml lipoprotein fractions was significantly lower. Glycated apoE was significantly higher in patients with hyperlipidaemia than healthy volunteers (p<0.0001). After 3 months treatment with niacin/LRPT, apoE in apoB?containing lipoproteins (VLDL+LDL) was significantly reduced, but was unchanged in apoA-containing lipoproteins (HDL) compared with treatment with placebo. Niacin/LRPT also had no effect on the elevated glycated apoE observed in patients with hyperlipidaemia.Conclusions: The effect of atorvastatin on total apoE concentration is dependent on the dose of atorvastatin and apoE genotype in patients with type 2 diabetes with nephropathy. Niacin/LRPT has no significant effect on total apoE and glycated apoE, but does influence their distribution in lipoprotein fractions in patients with hyperlipidaemia.

Association between apolipoprotein E gene polymorphism and hypertension in obstructive sleep apnea syndrome patients

Introduction Obstructive sleep apnea (OSA) is a common disorder with a high prevalence. There is increasing evidence to implicate OSA as a major risk factor for arterial hypertension, but to date a direct etiologic link between these diseases has not been established definitively. Although, several studies have shown that apolipoprotein E (ApoE) A genotypes have influence on the lipid metabolism, atherosclerosis and coronary artery diseases, is still no clear whether apoE gene is a predictor of hypertension. Few studies evaluated the influence of ApoE genotype on hypertension in sleep apnea patients. This study focused on investigates the association between APOE gene polymorphisms and arterial hypertension (AH) in OSA patients from Spain. Materials and methods APOE genotypes were obtained from 113 consecutively recruited patients with a diagnosis of OSA after polysomnography from the Sleep unit of the Rio Hortega Hospital. The following baseline variables were assessed: age (years), body mass index (kg/m2), (BMI), gender, alcohol intake (g/day), smoking status (never, current or former smoker) and use (packs-year). An AHI ⩾ 5 events per hour was considered as diagnostic of OSA. Results The prevalence of hypertension in OSA patients was 44.2%.The mean age of the OSA was 55.78 years and 16.8% were women. E3/E3 was the most common genotype: E3E3 (62.8%); E2E3 (14.2%), E3E4 (16.8%), E2E4 (6.2%). APOE E4 positive subjects only differ significantly from E4negative subjects in age (61.5 vs 54.6 years). OSA patients carrying the E3/E4 genotype showed an increased frequency of AH: OR 4.72 (CI 1.56–14.2 in unadjusted analyses. These findings keep significant even after correction for age, BMI, sex, AHI and cholesterol: 3.95 (CI 1.15–13.4).). We did not found a relationship between E3/E4 genotype with lipids profile in OSA patients. The mechanisms underlying this association are uncertain. Conclusion Our results strongly indicate that the presence of the E3/E4 genotype is associated with arterial hypertension in obstructive sleep apnea patients, even after adjusted for cardiovascular risk factors. Acknowledgements Acknowledgements to the sleep group of Hospital Rio Hortega and the Molecular Biology and genetics Institute.

Cholesterol in mild cognitive impairment and Alzheimer’s disease in a birth cohort over 14 years

Animal epidemiological and clinical studies suggest that cholesterol is a risk factor for Alzheimer's disease (AD). Nevertheless, the relation of cholesterol to mild cognitive impairment (MCI), influence of APOE genotype and its changes in lifespan is controversial. We investigated the potential impact of plasma total cholesterol (TC) on development of MCI and AD in the interdisciplinary longitudinal study on adult development and aging, a representative birth cohort (born 1930-1932), examined in 1993/1994 (VT1), 1997/1998 (VT2), and 2005/2007 (VT3). Of 500 participants at baseline, 381 survived and were examined at VT3. After exclusion of participants with lifetime prevalence of major psychiatric diseases or mild cognitive disorder due to a medical condition, 222 participants were included in the analysis. At VT3, 82 participants had MCI, 22 participants had AD, and 118 were in good health. Participants with MCI and AD at VT3 evidenced higher TC levels at VT1 than those who were healthy. Higher TC levels at baseline were associated with an increased risk for cognitive disorders at VT3 (highest vs. lowest quartile: OR 2.64, 95 % CI 1.12-6.23, p < 0.05). Over the 14 year follow-up, TC levels declined in those with MCI and AD, but remained stable in those who remained healthy. These findings were not modified by APOE genotype or use of cholesterol-lowering medications. Our findings demonstrate that higher TC levels are observed long before the clinical manifestation of MCI and AD in patients without psychiatric or somatic comorbidities and are independent of APOE genotype.

Effects of interactions between ApoE polymorphisms, alcohol consumption and obesity on age-related trends of blood pressure levels in postmenopausal women: The Bambuì cohort study of aging (1997–2008)

ObjectivesTo evaluate the effects of interactions between ApoE genotypes, alcohol consumption and obesity on the age-related trends of blood pressure (BP) levels in postmenopausal women. Study designA population-based prospective cohort study of all residents in Bambuì, south-eastern Brazil, aged 60 years or older. Repeated BP measurements were obtained in four waves from 851 women who underwent ApoE genotyping at baseline (88.3% of those enrolled), and multi-level random-effects pattern-mixture models were used to evaluate the age-related BP trajectories, while accounting for non-ignorable dropouts/deaths and handling heterogeneities as random parameter variations. The few measurements (2.1%) made during hormone replacement therapy were excluded from the analysis. ResultsAlcohol consumption was associated with high levels of systolic and diastolic BP in an age×genotype-dependent manner only in the non-obese women (BMI<27kg/m2). Among those with the ɛ3/3 genotype, the differences in systolic and diastolic levels between drinkers and non-drinkers estimated at the age of 60 years were respectively 13.7mmHg (p=0.022) and 10.7mmHg (p=0.002), and disappeared in the older age groups, in which drinking was associated with systolic/diastolic hypertension if the non-obese women were ɛ4 carriers. ConclusionIn non-obese postmenopausal women, alcohol consumption is associated with systolic and diastolic hypertension early in those with the ɛ3/3 ApoE genotype, and late in ɛ4 carriers. We hypothesize the mediation of androgen hormones and the influence of ApoE genotypes on age at natural menopause. A better understanding of these mechanisms may guide better preventive choices.

O3‐12‐05: Influence of APOE genotype on global and regional amyloid deposition: Results from three WW‐ADNI [C‐11]PiB data

O3‐12‐05: Influence of APOE genotype on global and regional amyloid deposition: Results from three WW‐ADNI [C‐11]PiB data