Is APOE ε4 required for Alzheimer's disease to develop in TREM2 p.R47H variant carriers?
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ABSTRACT:
SUBMITTER: Guerreiro R
PROVIDER: S-EPMC6380937 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We examined the impact of an APOE ε4 genotype on Alzheimer's disease (AD) subject platelet and lymphocyte metabolism. Mean platelet mitochondrial cytochrome oxidase Vmax activity was lower in APOE ε4 carriers and lymphocyte Annexin V, a marker of apoptosis, was significantly higher. Proteins that mediate mitophagy and energy sensing were higher in APOE ε4 lymphocytes which could represent compensatory changes and recapitulate phenomena observed in post-mortem AD brains. Analysis of the lipid synthesis pathway found higher AceCSI, ATP CL, and phosphorylated ACC levels in APOE ε4 lymphocytes. Lymphocyte ACC changes were also observed in post-mortem brain tissue. Lymphocyte RNAseq showed lower APOE ε4 carrier sphingolipid Transporter 3 (SPNS3) and integrin Subunit Alpha 1 (ITGA1) expression. RNAseq pathway analysis revealed APOE ε4 alleles activated inflammatory pathways and modulated bioenergetic signaling. These findings support a relationship between APOE genotype and bioenergetic pathways and indicate platelets and lymphocytes from APOE ε4 carriers exist in a state of bioenergetic stress. Neither medication use nor brain-localized AD histopathology can account for these findings, which define an APOE ε4-determined molecular and systemic phenotype that informs AD etiology.
| S-EPMC8135087 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) represents the most common form of dementia in elder populations with approximately 30 million cases worldwide. Genome wide genotyping and sequencing studies have identified many genetic variants associated with late-onset Alzheimer's disease (LOAD). While most of these variants are associated with increased risk of developing LOAD, only limited number of reports focused on variants that are protective against the disease.MethodsHere we applied a novel approach to uncover protective alleles against AD by analyzing genetic and phenotypic data in Mount Sinai Biobank and Electronic Medical Record (EMR) databases.ResultsWe discovered a likely loss-of-function small deletion variant in the caspase 7 (CASP7) gene associated with significantly reduced incidence of LOAD in carriers of the high-risk APOE ε4 allele. Further investigation of four independent cohorts of European ancestry revealed the protective effect of the CASP7 variant against AD is most significant in homozygous APOE ε4 allele carriers. Meta analysis of multiple datasets shows overall odds ratio = 0.45 (p = 0.004). Analysis of RNA sequencing derived gene expression data indicated the variant correlates with reduced caspase 7 expression in multiple brain tissues we examined.ConclusionsTaken together, these results are consistent with the notion that caspase 7 plays a key role in microglial activation driving neuro-degeneration during AD pathogenesis, and may explain the underlying genetic mechanisms that anti-inflammatory interventions in AD show greater benefit in APOE ε4 carriers than non-carriers. Our findings inform potential novel therapeutic opportunities for AD and warrant further investigations.
| S-EPMC4928152 | biostudies-literature
Project description:IntroductionPathogenesis of Alzheimer's disease (AD) in apolipoprotein E ε4 (APOE ε4) carriers remains unclear. We hypothesize that APOE isoforms have differential effects on synaptic function.MethodsWe compared levels of CSF neurogranin (Ng) between APOE ε4 carriers and noncarriers in 399 subjects with normal cognition, mild cognitive impairment (MCI), and AD. We examined associations between Ng levels and age, education, gender, CSF-Aβ42, and tau protein.ResultsNeurogranin levels were significantly higher in APOE ε4 carriers compared to APOE ε4 noncarriers with MCI. Levels of Ng between the APOE ε4 carriers and APOE ε4 noncarriers with AD did not differ. Ng levels were correlated with MMSE and levels of tau and Aβ42.DiscussionSignificantly higher CSF Ng levels in APOE ε4 carriers with MCI may reflect synaptic injury underlying early cognitive impairment. Neurogranin may be an early biomarker of AD and important for disease diagnosis and timing of intervention in APOE ε4 carriers.
| S-EPMC5742562 | biostudies-literature
Project description:APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and accounts for 50-65% of late-onset AD. Late-onset AD patients carrying or not carrying APOE ε4 manifest many clinico-pathological distinctions. Thus, we applied a weighted gene co-expression network analysis to identify specific co-expression modules in AD based on APOE ε4 stratification. Two specific modules were identified in AD APOE ε4 carriers and one module was identified in non-carriers. The hub genes of one module of AD APOE ε4 carriers were ISOC1, ENO3, GDF10, GNB3, XPO4, ACLY and MATN2. The other module of AD APOE ε4 carriers consisted of 10 hub genes including ANO3, ARPP21, HPCA, RASD2, PCP4 and ADORA2A. The module of AD APOE ε4 non-carriers consisted of 16 hub genes including DUSP5, TNFRSF18, ZNF331, DNAJB5 and RIN1. The module of AD APOE ε4 carriers including ISOC1 and ENO3 and the module of non-carriers contained the most highly connected hub gene clusters. mRNA expression of the genes in the cluster of the ISOC1 and ENO3 module of carriers was shown to be correlated in a time-dependent manner under APOE ε4 treatment but not under APOE ε3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers' module was correlated under APOE ε3 treatment but not under APOE ε4 treatment. The modules of carriers demonstrated genetic bases and were mainly enriched in hereditary disorders and neurological diseases, energy metabolism-associated signaling and G protein-coupled receptor-associated pathways. The module including ISOC1 and ENO3 harbored two conserved promoter motifs in its hub gene cluster that could be regulated by common transcription factors and miRNAs. The module of non-carriers was mainly enriched in neurological, immunological and cardiovascular diseases and was correlated with Parkinson's disease. These data demonstrate that AD in APOE ε4 carriers involves more genetic factors and particular biological processes, whereas AD in APOE ε4 non-carriers shares more common pathways with other types of diseases. The study reveals differential genetic bases and pathogenic and pathological processes between carriers and non-carriers, providing new insight into the mechanisms of the differences between APOE ε4 carriers and non-carriers in AD.
| S-EPMC4941795 | biostudies-literature
Project description:BackgroundLeukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.MethodsWe analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.ResultsAfter follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404-7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947-2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.ConclusionsOur findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.
| S-EPMC8283833 | biostudies-literature
Project description:Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10-4) and HAGH (β = 0.481, P = 7.20 × 10-4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10-3) and HAGH proteins (β = 0.506, P = 9.31 × 10-7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10-3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10-9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.
| S-EPMC7237496 | biostudies-literature
Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with a complex genetic etiology. Besides the apolipoprotein E ε4 (APOE ε4) allele, a few dozen other genetic loci associated with AD have been identified through genome-wide association studies (GWAS) conducted mainly in individuals of European ancestry. Recently, several GWAS performed in other ethnic groups have shown the importance of replicating studies that identify previously established risk loci and searching for novel risk loci. APOE-stratified GWAS have yielded novel AD risk loci that might be masked by, or be dependent on, APOE alleles. We performed whole-genome sequencing (WGS) on DNA from blood samples of 331 AD patients and 169 elderly controls of Korean ethnicity who were APOE ε4 carriers. Based on WGS data, we designed a customized AD chip (cAD chip) for further analysis on an independent set of 543 AD patients and 894 elderly controls of the same ethnicity, regardless of their APOE ε4 allele status. Combined analysis of WGS and cAD chip data revealed that SNPs rs1890078 (P = 6.64E-07) and rs12594991 (P = 2.03E-07) in SORCS1 and CHD2 genes, respectively, are novel genetic variants among APOE ε4 carriers in the Korean population. In addition, nine possible novel variants that were rare in individuals of European ancestry but common in East Asia were identified. This study demonstrates that APOE-stratified analysis is important for understanding the genetic background of AD in different populations.
| S-EPMC8134477 | biostudies-literature
Project description:BackgroundSubjective cognitive decline (SCD) is characterized by self-reported cognitive deficits without measurable cognitive impairment. It has been suggested that individuals with SCD exhibited brain structural alterations in widespread cortical thinning or gray matter loss in the medial temporal and frontotemporal regions. Apolipoprotein E (APOE) ε4 allele is thought to be a genetic marker associated with risk of SCD. Neuropsychiatric symptoms may provide insight in detecting higher-risk elders for early Alzheimer's disease as well. Therefore, we aim to explore the characteristics of brain morphology in SCD and to determine whether it is influenced by APOE ε4 as well as neuropsychiatric symptoms in SCD.MethodsA total of 138 cognitively normal older individuals from the SILCODE cohort underwent a clinical interview, neuropsychological assessments, a blood test, and MRI. A two-sample t-test was used to examine the cortex volume and bilateral cortical surface area alterations between SCD (n = 65) and controls (n = 73). A general linear model analysis was used to test for both main and interaction effects of clinical phenotype (SCD vs. controls) and APOE on global and regional cortex volume and bilateral cortical surface area and thickness. A multiple linear regression analysis was conducted to determine the effects of the APOE genotype on the relationships between morphometric features and neuropsychiatric symptoms in SCD.ResultsCompared with controls, individuals with SCD showed decreased total cortical volumes and cortical surface area. SCD APOE ε4 carriers showed additive reduction in the right cortical surface area. The evaluation scores of anxiety symptoms were negatively associated with the right cortical surface area in SCD APOE 4 non-carriers.ConclusionsIndividuals with SCD had an altered cortical surface area, and APOE genotype and anxiety symptoms are modified factors on the cortical surface area decrease in SCD.Trial registrationClinicalTrials.gov (Identifier: NCT03370744 ). Registered 15 March 2017.
| S-EPMC6547570 | biostudies-literature
Project description:A rare heterozygous TREM2 variant p.R47H (rs75932628) has been associated with an increased risk for Alzheimer's disease (AD). We aimed to investigate the clinical presentation, neuropsychological profile, and regional pattern of gray matter and white matter loss associated with the TREM2 variant p.R47H, and to establish which regions best differentiate p.R47H carriers from noncarriers in 2 sample sets (Spanish and Alzheimer's Disease Neuroimaging Initiative, ADNI1). This was a cross-sectional study including a total number of 16 TREM2 p.R47H carriers diagnosed with AD or mild cognitive impairment, 75 AD p.R47H noncarriers and 75 cognitively intact TREM2 p.R47H noncarriers. Spanish AD TREM2 p.R47H carriers showed apraxia (9 of 9) and psychiatric symptoms such as personality changes, anxiety, paranoia, or fears more frequently than in AD noncarriers (corrected p = 0.039). For gray matter and white matter volumetric brain magnetic resonance imaging voxelwise analyses, we used statistical parametric mapping (SPM8) based on the General Linear Model. We used 3 different design matrices with a full factorial design. Voxel-based morphometry analyses were performed separately in the 2 sample sets. The absence of interset statistical differences allowed us to perform joint and conjunction analyses. Independent voxel-based morphometry analysis of the Spanish set as well as conjunction and joint analyses revealed substantial gray matter loss in orbitofrontal cortex and anterior cingulate cortex with relative preservation of parietal lobes in AD and/or mild cognitive impairment TREM2 p.R47H carriers, suggesting that TREM2 p.R47H variant is associated with certain clinical and neuroimaging AD features in addition to the increased TREM2 p.R47H atrophy in temporal lobes as described previously. The high frequency of pathologic behavioral symptoms, combined with a preferential frontobasal gray matter cortical loss, suggests that frontobasal and temporal regions could be more susceptible to the deleterious biological effects of the TREM2 variant p.R47H.
| S-EPMC4253600 | biostudies-literature
Project description:BACKGROUND:A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer's disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer's disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. RESULTS:The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson's disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson's disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. CONCLUSIONS:Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson's disease in addition to Alzheimer's disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
| S-EPMC3691612 | biostudies-literature