Sex, racial/ethnic, and APOE‐ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging
Amalia PetersonAditi SatheYisu YangAlaina DurantNiranjana ShashikumarKimberly R. PechmanLogan DumitrescuKatherine A. GiffordShannon L. RisacherLori L. Beason‐HeldYang AnKurt SchillingBennett A. LandmanJulie A. SchneiderLisa L. BarnesDavid A. BennettAngela L. JeffersonSusan M. ResnickAndrew J. SaykinTimothy J. HohmanDerek B. Archer
0
Citation
0
Reference
10
Related Paper
Abstract:
Abstract Background There is growing recognition that white matter microstructural integrity is affected in Alzheimer’s disease. The goal of this study was to characterize sex, racial/ethnic, and apolipoprotein (APOE)‐ε4 allele differences in white matter integrity. Methods This study included participants from ADNI, BLSA, ROS/MAP/MARS, and VMAP, all longitudinal cohorts of aging. This combined dataset included 6,837 imaging sessions from 2,619 participants age 50+ with diffusion MRI (dMRI) and demographic and clinical data (60% female, 31.4% APOE‐ε4 carriers, 78.9% White). dMRI was preprocessed using the PreQual pipeline. Free‐water (FW) correction was used to generate FW and FW‐corrected intracellular metrics including fractional anisotropy (FA FWcorr ), mean diffusivity (MD FWcorr ), axial diffusivity (AxD FWcorr ), and radial diffusivity (RD FWcorr ). Conventional and FW‐corrected metrics were harmonized using the Longitudinal ComBat package. Linear mixed‐effects models related sex, race/ethnicity, and APOE‐ε4 allele status to longitudinal diffusion metrics in 48 white matter tracts, adjusting for age at baseline, sex, education, race/ethnicity, APOE‐ε4 carrier status, cognitive status at baseline, and converter status. All models were corrected for multiple comparisons using the FDR approach. Result Sex differences in white matter were most notable in projection tracts (Figure 1A) and were primarily in FW‐corrected metrics. Females had lower FA FWcorr and higher RD FWcorr , indicative of worse microstructure, but lower AxD FWcorr . This sex difference was most pronounced for FA FWcorr in the ventral premotor projection tract (p=1.53x10 ‐62 ). There were global differences in white matter integrity by race/ethnicity (Figure 1B). Non‐Hispanic White participants tended to have higher conventional FA, FA FWcorr and AxD FWcorr and lower RD FWcorr . There was no association between APOE‐ε4 status and white matter integrity and no significant sex x race/ethnicity, sex x APOE‐ε4, or race/ethnicity x APOE‐ε4 interactions for conventional or FW‐corrected metrics when corrected for multiple comparisons. Conclusion There were striking sex and racial/ethnic (but not APOE‐ε4) differences in white matter tract integrity in a large cohort of aging adults. Female participants tended to have measures reflective of worse white matter integrity, and non‐Hispanic White participants tended to have measures reflective of greater integrity. Additional research exploring the etiology of these differences will be important to better understand disparities in Alzheimer’s disease.Keywords:
White (mutation)
Longitudinal Study
Apolipoprotein E
While ethnic identity, ethnic relations, ethnic conflict, and immigration are increasingly important factors in national, regional, and international affairs, there are no definitions or criteria consistently applied to delineate ethnic groups in nation worldwide. Thus, in this article, I have examined the concept of ethnic groups and theories of ethnicity concisely, in the hope of promoting discussions of the theories of ethnicity, and popularizing those concepts of ethnic groups and ethnicity.
Ethnic history
Cite
Citations (0)
Objective To study the distribution of Apo E gene in patients with Alzheimer desease, and analyse the relation between them . Methods ApoE genotyes of patients with Alzheimer desease and age-matched healthy controls were determined by using the polymerphism technique,subsequently to require the ralation between ApoE allele and AD . Results ApoE e4 allele of patients with AD was 20.4%,which obviously was higher than 7.5% of cotrols, but e3 allele of patients with AD was 64.8%, which was lower than 83.2% of cotrols.Conclusions In ApoE allele, e4 allele is a genetic suscetible factor in AD,and e3 allele is a protection factor.
Apolipoprotein E
Cite
Citations (1)
Internalization of apoE-containing very low density protein (VLDL) by hepatocytes in vivo and in vitro leads to apoE recycling and resecretion. Because of the role of apoE in VLDL metabolism, apoE recycling may influence lipoprotein assembly or remnant uptake. However, apoE is also a HDL protein, and apoE recycling may be related to reverse cholesterol transport. To investigate apoE recycling, apoE−/− mouse hepatocytes were incubated (pulsed) with wild-type mouse lipoproteins, and cells and media were collected at chase periods up to 24 h. When cells were pulsed with VLDL, apoE was resecreted within 30 min. Although the mass of apoE in the media decreased with time, it could be detected up to 24 h after the pulse. Intact intracellular apoE was also detectable 24 h after the pulse. ApoE was also resecreted when cells were pulsed with HDL. When apoA-I was included in the chase media after a pulse with VLDL, apoE resecretion increased 4-fold. Furthermore, human apoE was resecreted from wild-type mouse hepatocytes after a pulse with human VLDL. Finally, apoE was resecreted from mouse peritoneal macrophages after pulsing with VLDL. We conclude that 1) HDL apoE recycles in a quantitatively comparable fashion to VLDL apoE; 2) apoE recycling can be modulated by extracellular apoA-I but is not affected by endogenous apoE; and 3) recycling occurs in macrophages as well as in hepatocytes, suggesting that the process is not cell-specific.
Apolipoprotein E
Internalization
Cite
Citations (46)
The strongest risk-determinant for the development of sporadic Alzheimer's disease (AD) is the polymorphic APOE gene. In humans APOE has three variants, APOEε2, APOEε3 and APOEε4 whereof the latter increases the risk of disease 4–15 fold in a dose-dependent manner whilst APOEε2 appears to be protective. The biological mechanisms underlying the modified risk of disease in APOEε2 and APOEε4 carriers are not known. We previously showed that APOEε4-carriers exhibit a prominent plasma apolipoprotein E (apoE) deficiency caused by a specific reduction of the apoE4 isoform. This apoE deficiency was not observed in cerebrospinal fluid. In cognitively intact APOEε3/ε4 carriers an increased relative ratio of plasma apoE4 to apoE3 correlated to glucose hypometabolism and gray matter volume reductions in brain areas most often affected in AD. Hence, we speculate that peripheral apoE levels are linked to processes driving the risk of developing AD brain pathology. In order to determine the cause of the observed phenotype of plasma apoE deficiency in APOEε4-carriers we aimed to investigate the expression of different APOE alleles in liver biopsies from individuals with an APOEε3/ε4 versus an APOEε2/ε3 genotype. Liver biopsies from liver explants were received from n=3 APOEε3/ε4 and n=3 APOEε2/ε3 carriers who had undergone liver transplantation at the Karolinska University Hospital in Sweden. Total RNA (≥80% in DV200 score) was isolated according to routine laboratory methods and used for RNA sequencing employing the high-throughput Illumina platform. Paired-end sequencing reads were aligned to the human reference genome (hg19), using TopHat, and gene counts for expression determined using HTseq-count. Differential expression between the genotype groups was calculated using DEseq2. Preliminary analyses revealed differential expression of n=624 genes between individuals with an APOEε3/ε4 versus an APOEε2/ε3 genotype. In total n=624 genes are differentially expressed in livers from APOEε3/ε4 versus APOEε2/ε3 carriers. Further analyses will reveal the identity of the differentially expressed genes and whether there is a specific difference in the expression of APOE alleles that could explain the observed APOEε4 related plasma apoE deficiency
Apolipoprotein E
Cite
Citations (0)
Apolipoprotein E（ApoE）は生体内において脂質代謝に重要であり，最近，骨代謝にも関わっていることが示されている．ApoEはチタン周囲の骨形成時に多く発現し，チタン上の培養骨芽細胞に添加すると骨形成が促進することが明らかとなっているが，チタン上の骨芽細胞のApoE発現についてはまだよく解っていない．今回，われわれは，チタン，カバーグラス，培養デッシュ上での骨芽細胞のApoE発現について比較検討し，ApoEの発現する意義について考察した．ラットもしくはマウス初代培養骨芽細胞様細胞とマウスの骨芽細胞株であるMC3T3-E1細胞をそれぞれの材料上で培養し，石灰化結節の形成量を調べるとともにApoEおよびオステオカルシン（OCN）のmRNA発現を半定量的RT-PCRならびに定量的Real-time PCRにて調べた．チタン，培養デッシュ上では石灰化結節の形成がみられたが，カバーグラス上では見られなかった．ApoEの発現もそれと同様にチタン，培養デッシュ上で認めたれたが，カバーグラス上では認められなかった．Real-time PCR解析でも，培養14，21日目ではチタン，培養デッシュ上ではApoE，OCNとも同程度の発現を示したが，カバーグラス上では，ApoE，OCNの発現はチタン上での発現と比較すると，ApoE（14日目：18%，21日目：29%），OCN（14日目：2%，21日目：12%）ともに低い値を示した．一方，MC3T3-E1細胞では通常の培養条件ではApoEの発現は認められなかったが，ApoE添加もしくは初代培養骨芽細胞様細胞のコンディションメディウムを加えた群ではApoEの発現が認められた．以上より，初代培養骨芽細胞様細胞は骨形成を生じるときにApoEも発現して局所の脂質代謝に関わるとともに，骨代謝にも関わっていることが示唆された．この発現は，チタン上の骨形成に特異的ではないが，骨形成に石灰化中期および後期のApoEの発現が強く関わっていることが示唆された．
Apolipoprotein E
Cite
Citations (0)
Apolipoprotein E (apoE) is associated with lipoproteins in the cerebrospinal fluid (CSF). APOE4 increases and APOE2 decreases the risk for Alzheimer disease (AD) compared to the risk associated with APOE3 Because apoE4 is less efficient at cholesterol efflux than apoE2 or apoE3 in vitro, we hypothesized that APOE genotype may affect apoE particle size in vivo and that these size differences may be related to AD risk. We used nondenaturing gel electrophoresis to test for differences in the size of apoE complexes in human CSF samples of various APOE genotypes and created profiles of each sample to compare the patterns of apoE distribution. For middle-aged adults with no dementia, APOE 2.3 individuals had significantly larger apoE complexes than APOE 3.3 subjects, who had significantly larger apoE complexes than APOE 3.4 and APOE 4.4 individuals. Similarly, in an independent cohort of older adults, CSF apoE complexes of APOE4-positive individuals were smaller than those of the APOE4-negative individuals. Compared to individuals with no dementia, those with the mildest stages of dementia had similar sized CSF apoE complexes. These results identify a novel phenotypic difference in the size of CSF apoE complexes in middle age that correlate with the risk of AD later in life.
Apolipoprotein E
Cite
Citations (58)
Abstract Background Restrictions on mouse models have significantly impacted research towards understanding the most common genotype contributing to dementia in the human population – APOE ε3/ε4 . To address this, as part of MODEL-AD, we created new versions of humanized APOE ε4 and APOE ε3 mice on a C57BL/6J background that allow for unrestricted distribution and breeding. Methods To determine similarities and differences between APOE ε3/ε4 and APOE ε4/ε4 risk genotypes, we analyzed peripheral lipid concentrations as well as performed unbiased transcriptional profiling of the cortex at two and four months of age, comparing APOE ε3/ε4 and APOE ε4/ε4 to the reference APOE ε3/ε3 . To further compare APOE genotypes, cohorts of APOE ε3/ε3 , APOE ε3/ε4 , and APOE ε4/ε4 mice were exercised by voluntary running from 1 month to 4 months of age. Results Cholesterol composition was significantly influenced by APOE genotype as early as 2 months, while triglycerides were affected by APOE genotype at 4 months. Importantly, RNA-sequencing of the cortex followed by linear modeling or weighted gene co-expression network analysis (WGCNA) revealed that the APOE ε3/ε4 genotype showed unique transcriptomic signatures to that of APOE ε4/ε4 . Functional enrichment of the APOE ε3/ε4 , but not APOE ε3/ε4 genotype, revealed sulfur and heparin binding as significant terms at 2 months, and extracellular matrix and blood coagulation at 4 months. Further, cell specific contributions of significant genes identified endothelial cells as overrepresented in the APOE ε3/ε4 but not APOE ε4/ε4 genotype. WGCNA analysis confirmed findings from linear modeling but also predicted that running at a young age affects myelination and gliogenesis across APOE genotypes. Conclusions In summary, APOE ε3/ε4 genotype-specific effects were observed in cortical transcriptional profiles, suggesting therapies aimed at modifying APOE biology to treat dementias may need to be targeted to specific APOE genotypes.
Apolipoprotein E
Cite
Citations (3)
The ε4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer's disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-β (Aβ) is rapidly removed from the plasma by the live
Apolipoprotein E
Gene knockin
Knockout mouse
Amyloid (mycology)
Cite
Citations (52)
The book Ethnic Groups and Their Culture,whose chief editor is Professor Xu Jie-shun,was published by the Heilongjiang People's Publishing House in 2006 and collected the relevant achievements of studies of ethnic groups of the contemporary anthropology researchers.The works provides the latest interpretation of ethnic groups study in the academic circle in China and falls into such sections as special articles,concept of ethnic groups,theory of ethnic groups,identity of ethnic groups,relations of ethnic groups and culture of ethnic groups.
Ethnic culture
Ethnic history
Cite
Citations (0)
Allele epsilon 4 of the apolipoprotein E (APOE) gene is associated with higher risk of Alzheimer's disease (AD) in many, though not all, ethnic groups. The APOE allele and genotype frequency distributions were studied in 207 AD patients without cerebrovascular disorders, 62 AD patients with cerebrovascular disorders (combined AD), and 206 control individuals (ethnic Russians from the Russian population). The frequency of allele epsilon 4 in patients with early-onset and late-onset AD was three times higher than in control individuals (p < 0.000001). Compared with control people, patients with cerebrovascular disorders displayed a twofold higher frequency of allele epsilon 4; the difference between the two groups was significant (p = 0.0019). Relative risk of AD in carriers of allele epsilon 4 was five times higher than in carriers of alleles epsilon 2 and epsilon 3 (p < 0.000001). Allele epsilon 2 had a protective effect with respect to AD onset until 65 years of age (p = 0.015). Thus, APOE allele epsilon 4 proved to be a universal factor of early-onset, late-onset, and combined AD in ethnic Russians from Russia.
Apolipoprotein E
Cite
Citations (15)