scholarly journals Immune response and endocytosis pathways are associated with the escape of Alzheimer’s Disease

2019 ◽  
Author(s):  
Niccolò Tesi ◽  
Sven J. van der Lee ◽  
Marc Hulsman ◽  
Iris E. Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Risk Scores ◽  
Integrative Framework ◽  
Amyloid Metabolism ◽  
Population Controls

AbstractThe risk to develop and escape Alzheimer’s disease (AD) is influenced by a constellation of genetic variants, each associated with specific molecular pathways. Different pathways may differentially contribute to the modification of the AD-risk. We studied the molecular mechanisms that explain the extreme ends of the cognitive spectrum by comparing pathway-specific polygenic risk scores (pathway-PRS) in individuals with AD and those who escaped AD until old age. We used 29 genetic variants associated with AD to calculate pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in patients with AD (N=1,909), population controls (N=1,654), and cognitively healthy centenarians who escaped AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and escaping AD (p<0.05). The pathway that contributed the most to the overall modulation of AD-risk was b-amyloid metabolism (32%), driven mainly by APOE variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (p<0.05), while specifically immune response (p=3.1×10−3) and endocytosis (p=3.8×10−4) associated with escaping AD. These pathways were the main contributors to the overall modulation of genetic risk of AD (41.3% and 21.4%, respectively). Our work suggests that immune response and endocytosis might be involved in general neuro-protective functions, and highlights the need to study these pathways, next to b-amyloid metabolism.

scholarly journals Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Niccolò Tesi ◽  
Sven J. van der Lee ◽  
Marc Hulsman ◽  
Iris E. Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Risk Scores ◽  
Study Cohort ◽  
Increased Risk ◽  
Amyloid Metabolism ◽  
Β Amyloid

Abstract Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

scholarly journals Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment

Brain ◽  
2018 ◽  
Vol 141 (12) ◽  
pp. 3457-3471 ◽  
Author(s):  
Jiayuan Xu ◽  
Qiaojun Li ◽  
Wen Qin ◽  
Mulin Jun Li ◽  
Chuanjun Zhuo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Major Depressive Disorder ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Depressive Disorder ◽  
Genetic Variants ◽  
Amnestic Mild Cognitive Impairment ◽  
Risk Scores ◽  
Major Depressive

Abstract Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer’s disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer’s disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer’s disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein–protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer’s disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer’s disease.

scholarly journals Alzheimer’s disease genetic risk and sleep phenotypes: association with more slow-waves and daytime sleepiness

2020 ◽  
Author(s):  
Vincenzo Muto ◽  
Ekaterina Koshmanova ◽  
Pouya Ghaemmaghami ◽  
Mathieu Jaspar ◽  
Christelle Meyer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Young Adults ◽  
Genetic Variants ◽  
Daytime Sleepiness ◽  
Sleep Disturbances ◽  
Cognitive Disorders ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Genome Wide

AbstractSleep disturbances and genetic variants have been identified as risk factors for Alzheimer’s disease. Whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset, is currently not known. We extensively phenotyped sleep under different sleep conditions and compute whole-genome Polygenic Risk Scores (PRS) for AD in a carefully selected homogenous sample of healthy 363 young men (22.1 y ± 2.7) devoid of sleep and cognitive disorders. AD PRS was associated with more slow wave energy, i.e. the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss. Furthermore higher AD PRS was correlated with higher habitual daytime sleepiness. These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and reinforce the idea that sleep may be an efficient intervention target for AD.

scholarly journals A Multiomics Approach to Heterogeneity in Alzheimer’s Disease: Focused Review and Roadmap

2019 ◽  
Author(s):  
AmanPreet Badhwar ◽  
G. Peggy McFall ◽  
Shraddha Sapkota ◽  
Sandra E. Black ◽  
Howard Chertkow ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
New Drugs ◽  
Data Driven ◽  
Risk Scores ◽  
Multiple Levels ◽  
Multimodal Biomarkers ◽  
Design And Testing ◽  
Key Pathways

AbstractEtiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimer’s disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput ‘omics’ are unbiased data driven techniques that probe the complex etiology of Alzheimer’s disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimer’s disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimer’s disease.

scholarly journals Manifestations of Alzheimer’s Disease Genetic Risk in the Blood: A Cross-Sectional Multi-Omic Analysis in Healthy Adults Aged 18-90+

2021 ◽  
Author(s):  
Laura M Heath ◽  
John C. Earls ◽  
Andrew T. Magis ◽  
Sergey A. Kornilov ◽  
Jennifer C. Lovejoy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Large Scale ◽  
Late Onset ◽  
Early Adulthood ◽  
Whole Genome Sequencing Data ◽  
Significant Finding ◽  
Functional Interpretation

Abstract Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed.Results: We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable.Conclusions: Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

scholarly journals Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure

2018 ◽  
Author(s):  
Zeran Li ◽  
Jorge L Del-Aguila ◽  
Umber Dube ◽  
John Budde ◽  
Rita Martinez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Neuronal Loss ◽  
Reference Panel ◽  
Cellular Composition ◽  
Cell Type ◽  
Large Bulk

AbstractAlzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the effects of brain cellular composition are often ignored in high-throughput molecular studies. We developed and optimized a cell-type specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. We found that neuronal and astrocyte proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1 or PSEN2 presented lower neurons and higher astrocytes proportions compared to sporadic AD. Similarly, the APOE ε4 allele also showed decreased neurons and increased astrocytes compared to AD non-carriers. On the contrary, carriers of variants in TREM2 risk showed a lower degree of neuronal loss than matched AD cases in multiple independent studies. These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-seq studies for cell composition, and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD.

scholarly journals Manifestations of genetic risk for Alzheimer’s Disease in the blood: a cross-sectional multi-omic analysis in healthy adults aged 18-90+

2021 ◽  
Author(s):  
Laura Heath ◽  
John C. Earls ◽  
Andrew T. Magis ◽  
Sergey A. Kornilov ◽  
Jennifer C. Lovejoy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Multiple Testing ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Cross Sectional ◽  
Risk Variants

AbstractDeeply phenotyped cohort data can elucidate differences associated with genetic risk for common complex diseases across an age spectrum. Previous work has identified genetic variants associated with Alzheimer’s disease (AD) risk from large-scale genome-wide association study meta-analyses. To explore effects of known AD-risk variants, we performed a phenome-wide association study on ~2000 clinical, proteomic, and metabolic blood-based analytes obtained from 2,831 cognitively normal adult clients of a consumer-based scientific wellness company. Results uncovered statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE). These effects were detectable from early adulthood. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. Sex-stratified GWAS results from an independent AD case-control meta-analysis supported sexspecific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. These analyses support evidence from previous functional genomics studies in the identification of a causal variant within the PILRA gene. Taken together, this study highlights clues to the earliest effects of AD genetic risk variants in individuals where disease symptoms have not (yet) arisen.

scholarly journals IPSC-derived neuronal cultures expressing the Alzheimer’s disease associated rare TREM2 R47H variant enables the construction of an Aβ-induced gene regulatory network

2019 ◽  
Author(s):  
Soraia Martins ◽  
Andreas Müller-Schiffmann ◽  
Martina Bohndorf ◽  
Wasco Wruck ◽  
Kristel Sleegers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Neuronal Cultures ◽  
Gene Regulatory

AbstractRecently, genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer’s disease (LOAD). One of them is the rare p.Arg47His (R47H) variant within triggering receptor expressed on myeloid cells 2 (TREM2), which has been shown to increase the risk for developing AD 2-3-fold. Here, we report the generation and characterization of a model of LOAD using lymphoblast-derived iPSCs from patients harbouring the R47H mutation in TREM2 (AD TREM2 iPSCs), as well as from control individuals without dementia (CON iPSCs). iPSCs efficiently differentiate into mature neuronal cultures and comparative global transcriptome analysis identified a distinct gene expression profile in AD TREM2 neuronal cultures. Furthermore, manipulation of the iPSC-derived functional neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD TREM2 neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER) which emphasised ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.

scholarly journals IPSC-Derived Neuronal Cultures Carrying the Alzheimer’s Disease Associated TREM2 R47H Variant Enables the Construction of an Aβ-Induced Gene Regulatory Network

2020 ◽  
Vol 21 (12) ◽  
pp. 4516
Author(s):  
Soraia Martins ◽  
Andreas Müller-Schiffmann ◽  
Lars Erichsen ◽  
Martina Bohndorf ◽  
Wasco Wruck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Neuronal Cultures ◽  
Gene Regulatory ◽  
Induced Pluripotent

Genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer´s disease (LOAD). The rare R47H variant within triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to increase the risk for developing Alzheimer’s disease (AD) 2–3-fold. Here, we report the generation and characterization of a model of late-onset Alzheimer’s disease (LOAD) using lymphoblast-derived induced pluripotent stem cells (iPSCs) from patients carrying the TREM2 R47H mutation, as well as from control individuals without dementia. All iPSCs efficiently differentiated into mature neuronal cultures, however AD neuronal cultures showed a distinct gene expression profile. Furthermore, manipulation of the iPSC-derived neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER), which emphasized ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.

Sign in / Sign up

Export Citation Format

Share Document