Biology subjects

Nho, K.

Publications and source records attributed to Nho, K..

24 records · Page 2Linked to original sources

bioRxiv2019

The Alzheimer’s Disease Metabolome: Effects of Sex and APOE ε4 genotype

Recent studies have provided evidence that late-onset Alzheimers disease (AD) can in part be considered a metabolic disease. Besides age, female sex and APOE {varepsilon}4 genotype represent strong risk factors for AD. They also both give rise to large metabolic differences, suggesting that metabolic aspects of AD pathogenesis may differ between males and females and between APOE {varepsilon}4 carriers and non-carriers. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 140 metabolites measured in serum samples of 1,517 AD neuroimaging initiative subjects, with AD biomarkers for A{beta} and tau pathology and neurodegeneration. We observed substantial sex differences in effects of 15 metabolites on AD biomarkers with partially overlapping differences for APOE {varepsilon}4 status groups. These metabolites highlighted several group-specific alterations not observed in unstratified analyses using sex and APOE {varepsilon}4 as covariates. Combined stratification by both variables uncovered further subgroup-specific metabolic effects limited to the group with presumably the highest AD risk: APOE {varepsilon}4+ females. Pathways linked to the observed metabolic alterations suggest that females experience more expressed impairment of mitochondrial energy production in AD than males. These findings indicate that dissecting metabolic heterogeneity in AD pathogenesis may enable grading of the biomedical relevance of specific pathways for specific subgroups. Extending our approach beyond simple one- or two-fold stratification may thus guide the way to personalized medicine.\n\nSignificance statementResearch provides substantial evidence that late-onset Alzheimers disease (AD) is a metabolic disease. Besides age, female sex and APOE{varepsilon}4 genotype represent strong risk factors for AD, and at the same time give rise to large metabolic differences. Our systematic investigation of sex and APOE {varepsilon}4 genotype differences in the link between metabolism and measures of pre-symptomatic AD using stratified analysis revealed several group-specific metabolic alterations that were not observed without sex and genotype stratification of the same cohort. Pathways linked to the observed metabolic alterations suggest females are more affected by impairment of mitochondrial energy production in AD than males, highlighting the importance of tailored treatment approaches towards a precision medicine approach.

bioinformatics↗

bioRxiv2019

Sets of Co-regulated Serum Lipids are Associated with Alzheimer Disease Pathophysiology

INTRODUCTIONAltered regulation of lipid metabolism in Alzheimer disease (AD) can be characterized using lipidomic profiling. METHOD349 serum lipids were measured in 806 participants enrolled in the Alzheimer Disease Neuroimaging Initiative Phase 1 (ADNI1) cohort and analysed using lipid regression models and lipid set enrichment statistics. RESULTSAD diagnosis was associated with 7 of 28 lipid sets of which four also correlated with cognitive decline, including polyunsaturated fatty acids. CSF amyloid beta A{beta}1-42 correlated with glucosylceramides, lysophosphatidyl cholines and unsaturated triacylglycerides; CSF total tau and brain atrophy correlated with monounsaturated sphingomyelins and ceramides, in addition to EPA-containing lipids. DISCUSSIONLipid desaturation, elongation and acyl chain remodeling are dysregulated across the spectrum of AD pathogenesis. Monounsaturated lipids were important in early stages of AD, while polyunsaturated lipid metabolism was associated with later stages of AD. SIGNFICANCEBoth metabolic genes and co-morbidity with metabolic diseases indicate that lipid metabolism is critical in the etiology of Alzheimers disease (AD). For 800 subjects, we found that sets of blood lipids were associated with current AD-biomarkers and with AD clinical symptoms. Our study highlights the role of disturbed acyl chain lipid remodelling in several lipid classes. Our work has significant implications on finding a cure for AD. Depending on subject age, human blood lipids may have different effects on AD development. Remodelling of acyl chains needs to be studied in relation to genetic variants and environmental factors. Specifically, the impact of dietary supplements and drugs on lipid remodelling must be investigated.

neuroscience↗

bioRxiv2018

Serum triglycerides in Alzheimer’s disease: Relation to neuroimaging and CSF biomarkers

ObjectiveTo investigate the association of triglyceride (TG) principal component scores with Alzheimers disease (AD) and the \"A/T/N/V\" (Amyloid, Tau, Neurodegeneration, and Cerebrovascular disease) biomarkers for AD.\n\nMethodsSerum levels of 84 TG species were measured using untargeted lipid profiling of 689 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) cohort including 190 cognitively normal older adults (CN) and 339 mild cognitive impairment (MCI) and 160 AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]FDG-PET) were assessed using a multivariate generalized linear model (GLM) approach. In both cases, the Bonferroni method of adjustment was employed to correct for multiple comparisons.\n\nResultsThe 84 TGs yielded 9 principal components, two of which consisting of long-chain, polyunsaturated fatty acid-containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying APOE {varepsilon}4 allele, these principal components were significantly associated with CSF amyloid-{beta}1-42 values and entorhinal cortical thickness.\n\nConclusionsThis study shows PUTG component scores significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE {varepsilon}4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.

neuroscience↗

bioRxiv2018

Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

Microglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. We assessed the effect of microglial activation in the aging human brain by calculating the proportion of activated microglia (PAM), based on morphologically defined stages of activation in four regions sampled postmortem from up to 225 elderly individuals. We found that cortical and not subcortical PAM measures were strongly associated with {beta}-amyloid, tau-related neuropathology, and rates of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE {varepsilon}4, the strongest genetic risk factor for Alzheimers disease. Mediation modeling suggests that PAM accelerates accumulation of tau pathology leading to cognitive decline, supporting an upstream role for microglial activation in Alzheimers disease. Genome-wide analyses identified a common variant (rs2997325) influencing cortical PAM that also affected in vivo microglial activation measured by positron emission tomography using [11C]-PBR28 in an independent cohort. Finally, we identify overlaps of PAMs genetic architecture with those of Alzheimers disease, educational attainment, and several other traits.

genomics↗

bioRxiv2018

Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer’s Disease: Relationship to Neuroimaging and CSF Biomarkers

IntroductionBile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimers disease (AD) including neuroinflammation and amyloid-{beta} deposition.\n\nMethodSerum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n=1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the \"A/T/N\" (Amyloid, Tau and Neurodegeneration) biomarkers for AD: CSF biomarkers, atrophy (MRI), and brain glucose metabolism ([18F]FDG-PET).\n\nResultsOf 23 BA and relevant calculated ratios, three BA signatures were associated with CSF A{beta}1-42 (\"A\") and three with CSF p-tau181 (\"T\") (corrected p<0.05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy (\"N\"), respectively (corrected p<0.05).\n\nConclusionThis is the first study to show serum-based BA metabolites are associated with \"A/T/N\" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.

neuroscience↗

bioRxiv2018

Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

IntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD).\n\nMethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing.\n\nResultsIn AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles.\n\nConclusionWe report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.

neuroscience↗