Function Of APOE Genotype Research Articles

Effects of sex and genotype in human APOE-targeted replacement mice on alcohol self-administration measured with the automated IntelliCage system before and after repeated mild traumatic brain injury.

Few studies have examined the association between APOE genotype and alcohol use. Although some of these studies have reported outcomes associated with a history of drinking, none have examined alcohol-seeking behavior. In addition, no preclinical studies have examined alcohol use as a function of APOE genotype with or without traumatic brain injury. Male and female human APOE3- and APOE4-targeted replacement (TR) mice were used to assess voluntary alcohol seeking longitudinally using a 2-bottle choice paradigm conducted within the automated IntelliCage system prior to and following repeated mild TBI (rmTBI). Following an acquisition phase in which the concentration of ethanol (EtOH) was increased to 12%, a variety of drinking paradigms that included extended alcohol access (EAA1 and EAA2), alcohol deprivation effect (ADE), limited access drinking in the dark (DID), and progressive ratio (PR) were used to assess alcohol-seeking behavior. Additional behavioral tasks were performed to measure cognitive function and anxiety-like behavior. All groups readily consumed increasing concentrations of EtOH (4-12%) during the acquisition phase. During the EAA1 period (12% EtOH), there was a significant genotype effect in both males and females for EtOH preference. Following a 3-week abstinence period, mice received sham or rmTBI resulting in a genotype- and sex-independent main effect of rmTBI on the recovery of righting reflex and a main effect of rmTBI on spontaneous home-cage activity in females only. Reintroduction of 12% EtOH (EAA2) resulted in a significant effect genotype for alcohol preference in males with APOE4mice displaying increased preference and motivation for alcohol compared with APOE3mice independent of TBI while in females, there was a significant genotype×TBI interaction under the ADE and DID paradigms. Finally, there was a main effect of rmTBI on increased risk-seeking behavior in both sexes, but no effect on spatial learning or cognitive flexibility. These results suggest that sex and APOE genotype play a significant role in alcohol consumption and may subsequently influence long-term recovery following traumatic brain insults.

Apolipoprotein E DNA methylation and late-life disease.

BackgroundThis study aims to investigate if DNA methylation of the apolipoprotein E (APOE) locus affects the risks of dementia, Alzheimeŕs disease (AD) or cardiovascular disease (CVD).MethodsDNA methylation across theAPOE gene has previously been categorized into three distinct regions: a hypermethylated region in the promoter, a hypomethylated region in the first two introns and exons and a hypermethylated region in the 3′exon that also harbours theAPOE ε2 and ε4 alleles. DNA methylation levels in leukocytes were measured using the Illumina 450K array in 447 Swedish twins (mean age 78.1 years). We used logistic regression to investigate whether methylation levels in those regions affect the odds of disease.ResultsWe found that methylation levels in the promoter region were associated with dementia and AD after adjusting for sex, age at blood draw, education, smoking and relatedness among twins [odds ratio (OR) 1.32 per standard deviation increase in methylation levels, 95% confidence interval (CI) 1.08–1.62 for dementia; OR 1.38, 95% CI 1.07–1.78 for AD). We did not detect any difference in methylation levels between CVD cases and controls. Results were similar when comparing within discordant twin pairs, and did not differ as a function ofAPOE genotype.ConclusionsWe found that higher DNA methylation levels in the promoter region ofAPOE increase the odds of dementia and AD, but not CVD. The effect was independent ofAPOE genotype, indicating that allelic variation and methylation variation inAPOE may act independently to increase the risk of dementia.

Differences in default network and episodic memory related brain activity as a function of apoe genotype in healthy young adults

Event Abstract Back to Event Differences in default network and episodic memory related brain activity as a function of apoe genotype in healthy young adults Reza Habib1* and Kit Elam2 1 Department of Psychology, Southern Illinois University Carbondale, United States 2 Centre for Research on Children and Families, University of Otago, New Zealand The presence of the E4 allele of the APOE gene has been shown to be a risk factor for the development of cognitive impairment and Alzheimer’s disease in elderly individuals. Few studies, however, have examined differences in behavior and brain activity as a function of APOE genotype in young, healthy adults. In the present study, brain activity, as measured with fMRI, was contrasted between n=10 young, healthy carriers of the E4 allele of the APOE gene and n=12 young, healthy non-carriers of the E4 allele during an associative recognition Episodic Memory task and a rest task designed to activate the brain’s Default Network. Corrected recognition performance did not significantly differ between carriers and non-carriers of the E4 allele. Significantly greater activity for hits than misses in non-carriers of the E4 allele was noted in the left inferior parietal lobule and the left parahippocampal gyrus. No such activity was observed for carriers of the E4 allele. Activity during the rest scan was noted in the left superior parietal lobule (BA 7) in non-carriers of the E4 allele. Activity in this component of the Default Network did not reach significance in carriers of the E4 allele. Instead, carriers of the E4 allele demonstrated activity in the rest scan bilaterally in the middle frontal gyrus. These results demonstrate that young, healthy carriers of the E4 allele, in the absence of behavioral differences, nevertheless demonstrate alterations in the brain networks involved in episodic memory retrieval and the Default Network. To the extent that activity within the memory system and the Default Network is altered in Alzheimer’s disease, these results suggest that precursors of this altered function may be present many years prior to the onset of Alzheimer’s disease. Keywords: APOE gene, E4 allele Conference: XI International Conference on Cognitive Neuroscience (ICON XI), Palma, Mallorca, Spain, 25 Sep - 29 Sep, 2011. Presentation Type: Symposium: Oral Presentation Topic: Symposium 12: Human genetics of cognition Citation: Habib R and Elam K (2011). Differences in default network and episodic memory related brain activity as a function of apoe genotype in healthy young adults. Conference Abstract: XI International Conference on Cognitive Neuroscience (ICON XI). doi: 10.3389/conf.fnhum.2011.207.00536 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 14 Nov 2011; Published Online: 28 Nov 2011. * Correspondence: Dr. Reza Habib, Department of Psychology, Southern Illinois University Carbondale, Illinois, United States, rhabib@siu.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Reza Habib Kit Elam Google Reza Habib Kit Elam Google Scholar Reza Habib Kit Elam PubMed Reza Habib Kit Elam Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

ApoE genotype and abnormal auditory cortical potentials in healthy older females

Apolipoprotein E (ApoE) status and gender are risk factors for the development of Alzheimer's disease. Alzheimer's disease is more prevalent in female relative to male carriers of the ApoE epsilon 4 gene. We examined cortical sensory (P50, N100) and cognitive (P300) potentials in an auditory target detection task in females as a function of ApoE genotype (ApoE epsilon 4 carriers, ApoE epsilon 4 non-carriers) to define the incidence of abnormalities prior to the clinical expression of cognitive impairments. Both neuropsychological test scores and sensory cortical potentials did not differ between the two ApoE groups. In contrast, cognitive P300 potentials were significantly decreased in amplitude and delayed in latency for ApoE epsilon 4 carriers compared to non-carriers. Four out of the 10 ApoE epsilon 4 carriers had abnormally (>2S.D.) delayed P300 latency compared to one out of 20 non-carriers. Abnormal cognitive processes reflected by P300 latency delays are expressed at significantly higher incidence in normal older females who are carriers of the epsilon 4 allele than in non-carriers of this allele.

P3-298: Changes in synaptic integrity as a function of APOE genotype and age

P3-298: Changes in synaptic integrity as a function of APOE genotype and age

Cerebral Cortical Arteriolar Angiopathy, Vascular Beta-Amyloid, Smooth Muscle Actin, Braak Stage, and APOE Genotype

We examined the associations among the vascular beta-amyloid levels, smooth muscle actin, wall thickness, and lumen diameter to achieve greater understanding of the arteriolar changes that accompany Alzheimer disease (AD). Post-mortem pathology brain specimens from 76 patients with AD and 19 non-AD age control subjects were studied. We analyzed arterioles of the frontal cortex (Brodmann area 10) by immunohistochemistry and morphometry, and derived measures of vascular beta-amyloid level, smooth muscle actin (SMA) volume, and arteriolar wall thickness and lumen diameter. APOE genotype was determined for each case. Overall, there was a striking reciprocal relationship between arteriolar beta-amyloid volume and smooth muscle actin (P<0.0001). In addition, there was a strong positive association between progressively accumulating vascular beta-amyloid and augmentations in both wall thickness (P<0.0001) and lumen width (P<0.0001). In comparison with non-AD control subjects, smooth muscle actin was decreased in patients clinically diagnosed with AD and was reduced >10-fold in cases with AD pathology (Braak I to VI) compared with those lacking AD neuropathology. Significantly altered composition and structure of cortical vessels in pre-Braak stages corroborated our hypothesis that arterioles are devastated early in the AD pathological process. Smooth muscle actin, arteriolar wall thickness, and luminal diameter did not vary with Braak stage severity (P>0.05), indicating that substantial arteriolar damage may precede at least some of the interstitial plaques and neuronal tangles. Moreover, the structural and biochemical arteriolar abnormalities did not vary as a function of APOE genotype (P>0.05). We postulate that in elderly patients, the continually progressing beta-amyloid-associated angiopathy, at the arteriolar level, harms the contractile apparatus and cerebral blood flow autoregulation, thereby making the downstream capillaries vulnerable to damage. Collectively, our observations lend further support to the idea that microvascular damage has a role, perhaps relatively early, in the onset of major AD pathology.

The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol

The apolipoprotein E4 ( APOE4) gene is a well-known risk factor for Alzheimer's disease (AD) and other neurological disorders. Post-menopausal women with AD who express at least one APOE4 gene have more severe neuropathology and worsened cognitive scores than their non-expressing counterparts. Since 17β-estradiol down-regulates inflammation as part of its neuroprotective role, we examined the effect of 17β-estradiol on the response of microglia to immune activation as a function of APOE genotype. Our data show that the anti-inflammatory activity of 17β-estradiol is significantly reduced in APOE4 targeted replacement mice compared to APOE3 mice. A significant interaction between APOE genotype and the response to 17β-estradiol was observed for NO and cytokine production by immune activated microglia. The genotype specific effect was not restricted to brain macrophages since peritoneal macrophages from APOE4 ovariectomized mice also demonstrated a significant difference in 17β-estradiol responsiveness. ERβ protein levels in APOE4 microglia were higher than APOE3 microglia, suggesting a difference in post-translational protein regulation in the presence of the APOE4 gene. Overall, our data indicate that the APOE genotype may be a critical component in assessing the effectiveness of 17β-estradiol's action and may impact the neuroprotective role of 17β-estradiol and of hormone replacement therapy on brain function when the APOE4 gene is expressed.

The Differential Benefits Of Aerobic Fitness For Cognitive Performance As A Function Of ApoE Genotype

The Differential Benefits Of Aerobic Fitness For Cognitive Performance As A Function Of ApoE Genotype

The Differential Benefits Of Aerobic Fitness For Cognitive Performance As A Function Of ApoE Genotype

The apolipoprotein E epsilon 4 (ApoE-ε4) allele is a common susceptibility gene for late-onset cognitive decline and Alzheimer's dementia (AD). However, since this gene is neither necessary nor sufficient for the development of these problems, it would be beneficial to identify risk modifiers, some of which may interact with ApoE-ε4 allele in the prediction of cognitive outcomes. Purpose: Therefore, the purpose of this study was to examine the effects of ApoE-ε4 gene dose, aerobic fitness (VO2max), and their interaction on cognitive measures hypothesized to be sensitive to the interaction. Methods: Data were collected from 85 cognitively normal older women (51–77 yrs, M = 61.8 yrs). Participants provided blood samples for ApoE genotypes, understood that they would receive no information about their ApoE genotypes, completed a battery of clinical ratings and neuropsychological tests, and performed a VO2max test. The sample included 7 ε4 homozygotes, 25 ε4 heterozygotes, and 53 ε4 non-carriers. Hierarchical regression analyses were conducted with depression, years of education, time between cognitive and fitness tests, and age entered first, followed by main effects for VO2max and ApoE-ε4 gene dose, followed by the interaction terms for VO2max by ApoE-ε4. Results: After controlling for main effects, the interaction of ApoE-ε4 gene dose by aerobic fitness predicted a significant (p < .05) percentage of the variance in performance (R2 = 7–9%) on several subscales of the Wechsler Adult Intelligence Scale (Perceptual Organization, Information, Block Design, Digit Symbol Substitution) and on the Complex Figures Test recall scale. Examination of the results indicated that the findings were consistent across all cognitive measures and were such that VO2max was positively related to cognitive performance for the ε4 homozygotes and was generally not related to performance for the ε4 heterozygotes or the ε4 non-carriers. Conclusion: These findings suggest that aerobic fitness is associated with better cognitive performance in homozygous carriers of a common AD susceptibility gene. Larger samples, our ongoing longitudinal assessments, the conductance of true-experimental studies, and the study of persons with other AD risk factors are needed to further demonstrate the protective effects of aerobic fitness on the subsequent development of cognitive decline and probable AD in persons at higher risk for these problems. Supported by NIA grants 1-R03AG022621 and P30 AG19610, NIMH grant RO1 MH057899, the Alzheimer's Association grants IIRG-98-068 and IIRG-98-078, the Arizona Alzheimer's Research Center, and the Arizona State University Stress Center.

Altered PET Functional Brain Responses in Cognitively Intact Elderly Persons at Risk for Alzheimer Disease (Carriers of the 4 Allele)

Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable. Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

APOE-dependent PET patterns of brain activation in Alzheimer disease.

Using H2(15)O PET, the authors imaged 13 patients with Alzheimer disease (AD) while performing a serial nonverbal recognition memory task. Patterns of brain activation differed as a function of APOE genotype: epsilon4 carriers exhibited lower activation in the left lingual gyrus and higher activation in left cuneus, precuneus, parahippocampal, and right precentral gyrus. The APOE genotype seems to play a role in cerebral physiologic activity even after onset of clinical manifestations of AD.

Increased CSF cortisol in AD is a function of APOE genotype.

Increased hypothalamic-pituitary-adrenal (HPA) axis activity manifested by elevated cortisol levels is observed in AD and may contribute to AD by lowering the threshold for neuronal degeneration. Presence of the APOE-epsilon4 allele increases risk for AD. Increased cortisol concentrations in apoE-deficient mice suggest that APOE genotype may influence cortisol concentrations in AD. The authors measured cortisol levels in CSF and determined APOE genotypes for 64 subjects with AD and 34 nondemented older control subjects. CSF cortisol was significantly higher in AD than in control subjects. CSF cortisol concentrations differed with respect to APOE genotype in both subjects with AD (epsilon4/epsilon4 > epsilon3/4epsilon > epsilon3/epsilon3) and normal older control subjects (epsilon3/epsilon4 > epsilon3/epsilon3 > epsilon2/epsilon3). Comparison of CSF cortisol concentrations within the epsilon3/epsilon4 and epsilon3/epsilon3 genotypes revealed no differences between AD and control subject groups. Higher CSF cortisol concentrations were associated with increased frequency of the APOE-epsilon4 allele and decreased frequency of the APOE-epsilon2 allele in AD subjects relative to control subjects. This effect of APOE genotype on HPA axis activity may be related to the increased risk for AD in persons carrying the APOE-epsilon4 allele and decreased risk for AD in persons carrying the APOE-epsilon2 allele.

ApoE, Alzheimer's disease, and recovery from brain stress.

Apolipoprotein E (APOE, gene; ApoE, protein) is the major genetic susceptibility locus for the common forms of Alzheimer's disease (AD). There are three common polymorphisms in the population: epsilon 2, epsilon 3, and epsilon 4. The inheritance of each dose of epsilon 4 increases the risk and lowers the age of onset distribution for AD; epsilon 2 lowers the risk and increases the age of onset distribution. APOE-epsilon 4 has a high positive predictive value for AD, and is clinically useful as an adjunct in the early diagnosis of cognitively impaired patients. The APOE alleles have also been associated with risk of AD with head injury, intraneuronal localization of ApoE in animal stroke models, recovery of function after intracerebral hemorrhage, and recovery of psychological parameters after general cardiac anesthesia. A multifunctional role of ApoE in the brain implicates isoform-specific differences in interactions with several brain proteins including A beta, tau, and MAP-2. Intraneuronal ApoE is increased temporally and in relevant neurons in AD as a function of APOE genotype. Decreased glucose metabolism can be demonstrated by PET imaging in subjects two decades before the median age of onset as a function of APOE genotype. ApoE isoforms may also have different effects as antioxidants. The risk of stroke and vascular dementia has not been confirmed in neuropathological series to be related to specific APOE genotypes.

The impact of apolipoprotein E4 on cause of death in Alzheimer's disease.

We tested the hypothesis that the apolipoprotein E epsilon 4 (apoE4) allele is associated with an increased proportion of vascular-related mortality in Alzheimer's disease (AD). ApoE4 is associated with an increased risk of developing AD, with an earlier onset, and may predispose to vascular dementia as well. In the general population, apoE4 has been associated with increased coronary artery disease and shorter lifespan. There is a paucity of data regarding the effect of the apolipoprotein E (apoE) genotype upon the contributing causes of death in AD. Death certificates of 114 AD cases were reviewed blind to apoE genotype. Deaths due to ischemic heart disease (IHD), cerebrovascular disease (CVD), vascular disease (either IHD or CVD), pneumonia, and other causes were analyzed as a function of apoE genotype. Logistic regression analyses were employed to control for age and gender effects. The likelihood of vascular disease contributing to death increased in association with the epsilon 4 allele (29% in cases without an epsilon 4 allele, 43% in cases with one epsilon 4 allele, 53% in epsilon 4/4 homozygous cases; p = 0.035 after corrections for age and gender). This increase appeared largely due to an increase in ischemic heart disease, which was reported more frequently on death certificates of cases with one or more epsilon 4 allele (adjusted odds ratio [OR] = 1.85 per epsilon 4 allele; p < 0.05). There were nonsignificant trends for apoE4 to be associated with increased mortality related to cerebrovascular disease (OR = 1.45) and decreased mortality related to pneumonia (OR = 0.77) and AD itself (OR = 0.72). The epsilon 4/4 cases had significantly earlier age of onset (mean = 64.5 yr), earlier death, and longer duration of disease (mean = 10.1 yr). Cases with one or more epsilon 4 allele tended to have lower mean MMSE scores prior to death (6.6 versus 9.5) and were more often female (54% versus 45%). The apoE4 allele appears to increase the risk of vascular and ischemic heart disease-related death in patients with AD.

The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant.

To determine the relationship between apolipoprotein E (apoE) genotype and neuropathologic lesions in Alzheimer's disease (AD) and Lewy body variant (LBV). Retrospective genetic-neuropathologic study of AD and LBV cases. The main neuropathologic outcome measures were modeled as a function of apoE genotype, neuropathologic diagnosis, and gender. Age at death and duration of symptom effects were controlled for by ANCOVA. One hundred twenty-seven cases with neuropathologically diagnosed AD (n = 84) or LBV (n = 43). Quantitative scores of neuritic plaques (NPs), neurofibrillary tangles (NFTs), cerebral amyloid angiopathy (CAA) severity, and CAA prevalence were averaged across four brain regions: midfrontal, inferior parietal, superior temporal, and hippocampal. The apoE epsilon 4 allele was associated with increased NPs within both AD and LBV. The epsilon 4 allele was associated with an increased frequency of CAA in the AD and LBV groups combined groups combined and in and in LBV alone. While CAA severity and NETs were increased in the epsilon 4/4 homozygous case when AD and LBV were combined, there were no significant effects within AD or LBV alone. The apoE epsilon 4 allele is strongly associated with increased NPs, but not neocortical NFTs, in both AD and LBV.

Apolipoprotein E genotyping in Alzheimer's disease

Apolipoprotein E ( APOE=gene; apoE=protein) is the first identified genetic susceptibility factor for sporadic Alzheimer's disease (AD). The application of APOE genotyping to the prediction and diagnosis of AD has been a source of controversy for the public and for clinicians and scientists. These issues were explored by a 33 member working group in a two-day conference held in October, 1995, and sponsored by the National Institute on Aging, the Alzheimer's Association (USA), and other organisations. The group's conclusions are: • The use of APOE genotyping to predict future risk of AD in symptom-free individuals is not recommended at this time. • Insofar as patients with AD are more likely to have an APOE-ϵ 4 allele than are patients with other forms of dementia or individuals without dementia, physicians may choose to use APOE genotyping as an adjunct to other diagnostic tests for AD. • Since genotyping cannot provide certainty about the presence or absence of AD, it should not be used as the sole diagnostic test. • In deciding whether or not to carry out APOE genotyping for any purpose, physicians and patients should bear in mind that genotype disclosure can have adverse effects on insurability, employability, and the psychosocial status of patients and family members. • Clinical and research applications of APOE genotyping must be linked to adequate pre-test and post-test counselling, education, and psychosocial support. • Research priorities include large-scale, prospective investigations of dementia incidence as a function of APOE genotype, and the development of novel approaches to the prevention and treatment of AD based on knowledge of the role in the disorder played by APOE and other factors.

Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease.

This study examines the relationship between the levels of apolipoprotein E (apoE) and apolipoprotein J (apoJ, also designated as clusterin) as a function of apoE genotype in the hippocampus and cortex of Alzheimer disease (AD) subjects. These two lipophilic proteins which are involved in the maintenance of lipid homeostasis are both synthesized in the brain by astrocytes. Results indicate a reduction of apoE levels in the hippocampus and frontal cortex that is proportional to the apoE4 allele dose. Conversely, apoJ (clusterin) levels were found to increase proportionately to the number of apoE4 allele dose. These results suggest a compensatory induction of apoJ (clusterin) in the brain of apoE4 AD subjects showing low brain levels of apoE.