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 A multiomics approach to heterogeneity in Alzheimer’s disease: focused review and roadmap

Brain ◽  
2019 ◽  
Vol 143 (5) ◽  
pp. 1315-1331 ◽  
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

Abstract Aetiological 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 aetiology 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 The genetic risk of Alzheimer’s disease beyond APOE ε4: systematic review of Alzheimer’s genetic risk scores

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Hannah Stocker ◽  
Tobias Möllers ◽  
Laura Perna ◽  
Hermann Brenner
Keyword(s):  
Systematic Review ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Risk Scores ◽  
Genetic Risk Scores ◽  
Apoe Ε4

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 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 Effect of Polygenic Score on Alzheimer’s Disease Risk Depends on Age and APOE Status

2020 ◽  
Author(s):  
Brian Fulton-Howard ◽  
Alison M. Goate ◽  
Robert P. Adelson ◽  
Jeremy Koppel ◽  
Marc L. Gordon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Disease Risk ◽  
Age Of Onset ◽  
Low Cost ◽  
Screening Method ◽  
Disease Onset ◽  
Risk Scores ◽  
Cross Sectional

AbstractPolygenic risk scores (PRS) have the potential to serve as a low-cost, non-invasive screening method for Alzheimer’s disease (AD). However, to what extent age and the Apolipoprotein E-ε4 (APOE4) risk allele influence the effect of PRS is underexplored. In a cohort of 346 superager controls (age ≥ 90 years), 2,930 controls (age 60-89) and 1,760 AD cases, we computed APOE-independent PRS for AD. When using superager controls, subjects with PRS in the top decile had nearly five times greater odds of having AD than subjects in the lowest decile (OR=4.91, P=2.24×10−6). In our cross-sectional cohort, PRS modifies the age of onset for AD among APOE4 carriers, but not among non-carriers. Among APOE4 carriers, PRS in the top decile was associated with a five years earlier AD onset than the lowest decile (70.0 vs 75.0 years; t-test P=2.4×10−5). These findings suggest that APOE-independent genetic risk disproportionally affects younger APOE4 carriers, leading to earlier disease onset, while older controls carry less genetic risk.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

2018 ◽  
Vol 16 (1) ◽  
pp. 49-55 ◽  
Author(s):  
J. Stenzel ◽  
C. Rühlmann ◽  
T. Lindner ◽  
S. Polei ◽  
S. Teipel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
New Drugs ◽  
Imaging Data ◽  
Wild Type ◽  
Preclinical Research ◽  
Standardized Uptake Values ◽  
Pet Ct

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [<sup>18</sup>F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [<sup>18</sup>F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [<sup>18</sup>F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [<sup>18</sup>F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [<sup>18</sup>F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [<sup>18</sup>F]-florbetaben in the APPswe/PS1dE9 mouse model.

scholarly journals Genetic risk for Alzheimer's disease, cognition, and mild behavioral impairment in healthy older adults

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Byron Creese ◽  
Ryan Arathimos ◽  
Helen Brooker ◽  
Dag Aarsland ◽  
Anne Corbett ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Behavioral Impairment ◽  
Healthy Older Adults

scholarly journals Interaction of Alzheimer’s Disease-Associated Genetic Risk with Indicators of Socioeconomic Position on Mild Cognitive Impairment in the Heinz Nixdorf Recall Study

2021 ◽  
pp. 1-11
Author(s):  
Mirjam Frank ◽  
Jonas Hensel ◽  
Lisa Baak ◽  
Sara Schramm ◽  
Nico Dragano ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Socioeconomic Position ◽  
Genetic Risk ◽  
Late Onset ◽  
Heinz Nixdorf Recall Study ◽  
Low Education ◽  
Additive Scale

Background: The apolipoprotein E (APOE) ɛ4 allele is reported to be a strong genetic risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Additional genetic loci have been detected that influence the risk for late-onset AD. As socioeconomic position (SEP) is also strongly related to cognitive decline, SEP has been suggested to be a possible modifier of the genetic effect on MCI. Objective: To investigate whether APOE ɛ4 and a genetic sum score of AD-associated risk alleles (GRSAD) interact with SEP indicators to affect MCI in a population-based cohort. Methods: Using data of 3,834 participants of the Heinz Nixdorf Recall Study, APOE ɛ4 and GRSAD by SEP interactions were assessed using logistic regression models, as well as SEP-stratified genetic association analysis. Interaction on additive scale was calculated using the relative excess risk due to interaction (RERI). All analysis were additionally stratified by sex. Results: Indication for interaction on the additive scale was found between APOE ɛ4 and low education on MCI (RERI: 0.52 [95% -confidence interval (CI): 0.01; 1.03]). The strongest genetic effects of the APOE ɛ4 genotype on MCI were observed in groups of low education (Odds ratio (OR): 1.46 [95% -CI: 0.79; 2.63] for≤10 years of education versus OR: 1.00 [95% -CI: 0.43; 2.14] for≥18 years of education). Sex stratified results showed stronger effects in women. No indication for interaction between the GRSAD and SEP indicators on MCI was observed. Conclusion: Results indicate that low education may have an impact on APOE ɛ4 expression on MCI, especially among women.

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