Biology subjects

Alzheimer's Disease Metabolomics Consortium,

Publications and source records attributed to Alzheimer's Disease Metabolomics Consortium,.

4 recordsLinked to original sources

bioRxiv2025

Metabolic Alteration in Oxylipins and Endocannabinoids Point to an Important Role for Soluble Epoxide Hydrolase and Inflammation in Alzheimer's Disease - Finding from Alzheimer's Disease Neuroimaging Initiative.

Mounting evidence implicates inflammation as a key factor in Alzheimers disease (AD) development. We previously identified pro-inflammatory soluble epoxide hydrolase (sEH) metabolites to be elevated in plasma and CSF of AD patients and to be associated with lower cognition in non-AD subjects. Soluble epoxide hydrolase is a key enzyme converting anti-inflammatory epoxy fatty acids to pro-inflammatory diols, reported to be elevated in multiple cardiometabolic disorders. Here we analyzed over 700 fasting plasma samples from the baseline of Alzheimers Disease Neuroimaging Initiative (ADNI) 2/GO study. We applied targeted mass spectrometry method to provide absolute quantifications of over 150 metabolites from oxylipin and endocannabinoids pathway, interrogating the role for inflammation/immune dysregulation and the key enzyme soluble epoxide hydrolase in AD. We provide further insights into the regulation of this pathway in different disease stages, APOE genotypes and between sexes. Additionally, we investigated in mild cognitive impaired (MCI) patients, metabolic signatures that inform about resilience to progression and conversion to AD. Key findings include I) confirmed disruption in this key central pathway of inflammation and pointed to dysregulation of sEH in AD with sex and disease stage differences; II) identified markers of disease progression and cognitive resilience using sex and ApoE genotype stratified analysis highlighting an important role for bile acids, lipid peroxidation and stress response hormone cortisol. In conclusion, we provide molecular insights into a central pathway of inflammation and links to cognitive dysfunction, suggesting novel therapeutic approaches that are based on targeting inflammation tailored for subgroups of individuals based on their sex, APOE genotype and their metabolic profile.

neuroscience↗

bioRxiv2025

APOE Genotype Influences on The Brain Metabolome of Aging Mice - Role for Mitochondrial Energetics in Mechanisms of Resilience in APOE2 Genotype.

Alzheimers disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid {beta}-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid {beta}-oxidation.

systems biology↗

bioRxiv2025

Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition

Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimers disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the "sphingolipid rheostat", reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals.

neuroscience↗

bioRxiv2020

Serum Metabolites Associate with Brain Amyloid Beta Deposition, Cognitive Dysfunction, and Alzheimers Disease Progression

RATIONALEMetabolomics in the Alzheimers Disease Neuroimaging Initiative (ADNI) cohort provides a powerful tool for mapping biochemical changes in AD, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-{beta} deposition in AD. OBJECTIVESWe examined 140 serum metabolites and their associations with brain amyloid-{beta} deposition, cognition, and conversion from mild cognitive impairment (MCI) to AD. FINDINGSSerum-based targeted metabolite levels were measured in 1,531 ADNI participants. We performed association analysis of metabolites with brain amyloid-{beta} deposition measured from [18F] Florbetapir PET scans. We identified nine metabolites as significantly associated with amyloid-{beta} deposition after FDR-based multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-{beta} accumulation. However, higher levels of seven phosphatidylcholines (PC) were associated with increased amyloid deposition. In addition, PC ae C44:4 was significantly associated with cognition and conversion from MCI to AD dementia. CONCLUSIONPerturbations in PC and acylcarnitine metabolism may play a role in features intrinsic to AD including amyloid-{beta} deposition and cognitive performance.

neuroscience↗