PubMed

Alzheimers Dement. 2024 Dec;20 Suppl 2:e092268. doi: 10.1002/alz.092268.ABSTRACTBACKGROUND: There is evidence indicating that disruptions in lipid metabolism are implicated in the pathophysiology of Alzheimer's disease (AD), with systemic repercussions that can be identified in peripheral blood. Recent studies conducted by our group have identified abnormalities in lipid metabolism among patients with mild cognitive impairment (MCI) and dementia (probable AD), through the investigation of a specific panel of lipid metabolites in plasma. Although much remains to be elucidated about the complex interaction between disturbances in lipid metabolites and the pathogenesis of AD, this promising research area offers exciting opportunities for the development of new strategies for disease diagnosis, treatment, and prevention.METHOD: Blood plasma samples were collected from the following groups: individuals with Alzheimer's disease (AD, n=17), individuals with Mild Cognitive Impairment (MCI) showing pathological AD signature (n=17), individuals with MCI without pathological AD signature (n=17), individuals with Down syndrome (n=17), elderly (n=17), and young (n=17) cognitively healthy individuals. We used liquid chromatography coupled with mass spectrometry (LC-MS/MS) for lipidomic analysis.RESULT: A total of 29 lipids were identified by principal component analysis (PCA) from a dataset consisting of 208 lipids. The lipid modules (attached image) composed of lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and sphingomyelin are differentially expressed in the samples. PCA1 (74.92%) and PCA2 (27.6%) account for the majority of variance in the sample (attached table).CONCLUSION: Our preliminary findings suggest that the use of PCA analysis may aid in discriminating differently expressed lipids in the plasma of individuals with dementia syndromes.PMID:39785405 | DOI:10.1002/alz.092268

Alzheimers Dement. 2024 Dec;20 Suppl 2:e093365. doi: 10.1002/alz.093365.ABSTRACTBACKGROUND: The study of new blood biomarkers in addition to amyloid beta and hyperphosphorylated tau is fundamental to expanding the understanding of the pathophysiology of dementia, especially Alzheimer`s disease, in search of therapeutic approaches.METHOD: In this study, we included individuals diagnosed with Alzheimer disease (AD), Mixed-type dementia (MD), Vascular dementia (VD) and a control group of cognitively healthy individuals. Demographics, clinical characteristics, neuroimages and plasma samples were collected. We performed a metabolomic aminoacid analysis using High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS/MS). Analyses were performed with GraphPad Prism 9.0 (GraphPad Software, San Diego, USA) or SPSS v. 18 software. Depending on the group comparison type, one-way analysis of variances with post-hoc Tukey-HSD test or independent samples t-tests. We compared aminoacid levels between the different groups (controls, AD, MD or VD) and dementia severity, assessed by Clinical Dementia Rating (CDR) score.RESULT: 135 individuals were clinically assessed as 33 controls, 42 AD, 41 MD and 19 VD. There was a statistically significant difference between controls and individuals with dementia in the following amino acids: aspartic acid (p<0.0001), arginine (p<0.0001), glutamic acid (p<0.0001), glutamine (p<0.0001), isoleucine (p<0.0008), leucine (p<0.0001). However, only arginine proved to be a biomarker capable of differentiating AD from DV (p<0.0003) CONCLUSION: These preliminary analyses show that leucine, isoleucine and glutamine were reduced in the plasma of patients with dementia, while aspartic acid, glutamic acid and arginine were increased. These markers can help us identify the underlying metabolic dysfunctions of different signaling pathways relevant to neuroprotection and vascular function.PMID:39785298 | DOI:10.1002/alz.093365

Alzheimers Dement. 2024 Dec;20 Suppl 7:e088163. doi: 10.1002/alz.088163.ABSTRACTBACKGROUND: Dietary factors are modifiable risk factors for dementia. In particular, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been associated with better cognitive function and lower risk of dementia. However, circulating metabolomic characteristics of the MIND diet and its associations with cognitive function remains unclear.METHOD: In the current study, 45906 UK Biobank (UKB) participants (mean age: 56.4 years) were separated into a discovery cohort and an internal prospective validation cohort, and 6193 Whitehall II (WHII) study participants (mean age: 56.8 years) constituted an external validation cohort. We identified the metabolites associated with the alternate MIND diet score (aMIND) using linear regression models, and Benjamini-Hochberg method was applied to control false discovery rate. We constructed a metabolomic signature score of the MIND diet using elastic net model and assessed the potential mediating role of the metabolomic signature in the associations of the aMIND with cognitive outcomes in the two cohorts.RESULT: The aMIND showed significant associations with 149 out of 168 (89%) metabolites in the UKB discovery cohort, and 47 of these associations were also replicated in both the internal validation cohort and the external validation cohort, including 38 lipoprotein subclass, 4 fatty acid, 1 cholesterol, 1 inflammation, 2 lipoprotein particle size, and 1 triglyceride measures. The metabolomic signature score based on the selected metabolites was significantly correlated with the aMIND (Pearson's r = 0.36, 0.31, and 0.27 in the discovery, internal validation and external validation cohort). In the UKB (491 incident dementia cases during a median follow-up of 11.8 years), but not WHII (169 in 17.8 years), the MIND metabolomic signature score significantly mediated the association of the aMIND and incident dementia by 45%. In the WHII, association between the aMIND and cognitive function was partially mediated by the metabolomic signature (proportion = 19%, P for mediation = 0.039).CONCLUSION: MIND diet was favourably associated with a panel of metabolites, and a MIND diet metabolomic signature score partially mediated the observed associations between MIND diet adherence and incident dementia and cognitive function.PMID:39784744 | DOI:10.1002/alz.088163

Alzheimers Dement. 2024 Dec;20 Suppl 7:e087444. doi: 10.1002/alz.087444.ABSTRACTExposure to environmental chemicals has been associated with Alzheimer's disease (AD); however, most studies have used a targeted approach to study this relationship. While targeted approaches have been critical to understand mechanisms, they do not reflect real world exposures where an individual is exposed to multiple chemicals at the same time. Exposomics provides the opportunity to use an -omics level approach to understand the environmental drivers of disease by measuring the burden of multiple chemicals at the same time. Using an exposomic approach, we found a metabolite of the legacy pesticide DDT to be associated with AD in an observational study. We then investigated whether DDT can exacerbate AD-related pathology using a transgenic strain of the nematode model Caenorhabditis elegans (worm) that expresses a mutant tau protein fragment that is prone to aggregation. Exposure to 3µM DDT resulted in internal levels of 0.5 pg (SD: 0.01) p, p'-DDT per worm and 0.1 pg (SD: 0.01) of its metabolite p, p'-DDE. We found that exposure DDT significantly restricted growth in the transgenic strain more than it does in wildtype worms. Further, DDT significantly lowered mitochondrial respiration rates in both strains. High-resolution mass spectrometry-based metabolomics (HRMS) analysis using the whole worm showed reduced levels of several amino acids and an increase in adenosylselenohomocysteine in DDT exposed worms. DDT exposure in the transgenic strain significantly increased the amount of time spent curling. The curling phenotype has been previously associated with mitochondrial dysfunction. Our data suggest that low level exposure to DDT likely exacerbates the mitochondrial inhibitory effects of aggregating tau protein in C. elegans. We are investigating the relationship between persistent organic pollutants and age-related cognitive decline in the Reference Ability Neural Network study. This study, conducted in healthy volunteers, allows us to consider the relationship between exposure and poor cognitive function without confounding by underlying disease. We plan to investigate the potential mechanism through which these chemicals affect neuronal health while considering them as a mixture using C. elegans. Recent advancements in predictive toxicology provide a starting point to consider the appropriate health and functional end points that should be investigated.PMID:39784694 | DOI:10.1002/alz.087444

Alzheimers Dement. 2024 Dec;20 Suppl 7:e091942. doi: 10.1002/alz.091942.ABSTRACTBACKGROUND: The Coaching for Cognition in Alzheimer's (COCOA) Trial was a prospective RCT testing a remotely coached multimodal lifestyle intervention for participants early on the Alzheimer's disease spectrum. Intervention focused on diet, exercise, cognitive training, sleep, stress, and social engagement. Enrollment criteria targeted individuals with cognitive decline who were able to engage remotely with a professional coach. COCOA demonstrated cognitive and functional benefits. Dense omics data were collected on 53 individuals (≥ 58 years).METHODS: We sought to identify blood analytes that mediated the effects of specific elements of the multimodal intervention on specific outcomes. Outcomes were assessed with the MCI Screen (MCIS) and the Functional Assessment Staging Tool (FAST). We combined these and other measures with proteomics and metabolomics data. We analyzed the resulting dataset of over 300,000 distinct molecular data points-reflecting over 1400 measures- assayed over a period of two years. We used MEGENA to hierarchically multiscale cluster analytes based on correlated responses and identified individual metabolites and functional clusters associated with each intervention and outcome. We analyzed individual time courses of key analyte mediators to illustrate personalized effects of interventions and individualized functional and cognitive outcomes.RESULTS: Distinct sets of correlated serum analytes ("communities") convey effects to functional (FAST) outcome and to cognitive (MCIS) outcome. Distinct communities respond to different modalities of intervention. Participants followed different aspects of the multimodal recommendations to different extents, and the analytes in their blood also responded idiosyncratically; analyte trajectories in different individuals show distinct dynamics. We made personalized predictions of future inflections in outcome based on observed changes in key serum mediators. We validated results with data from the Precision Recommendations for Environmental Variables, Exercise, Nutrition and Training Interventions to Optimize Neurocognition (PREVENTION) Trial.CONCLUSIONS: Lifestyle interventions have profound effects on blood metabolites (Figure 1). These in turn convey subtler specific effects to cognition and broad-based effects to function. Pathways that ameliorate the impact of AD via lifestyle interventions in some individuals include nitrogen subsystems, kidney function, and mitochondrial metabolism. These highlight the importance of clinical attention to overall health spanning multiple organ systems in individuals across the Alzheimer's disease spectrum.PMID:39784630 | DOI:10.1002/alz.091942

Alzheimers Dement. 2024 Dec;20 Suppl 7:e089878. doi: 10.1002/alz.089878.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with significant environmental factors, including diet, that influence its onset and progression. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored the KD's molecular impact for markers of AD therapeutic potential. The BEAM diet study simultaneously profiled the KD's effect on the lipidome, blood and cerebrospinal metabolome, and microbiome of both cognitively impaired and cognitively normal individuals. The findings summarized here assess the biological impact of a Modified Mediterranean KD in the context of Alzheimer's disease treatment and prevention.METHOD: BEAM involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean-ketogenic diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed HPLC-MS/MS lipidomics profiling in plasma, nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF, and metagenomics profiling on fecal samples before and after each diet to assess dietary-induced changes.RESULT: The MMKD led to significant alterations in the blood, CSF, and microbiome. These changes included a global elevation across all plasmanyl and plasmenyl ether lipid species, improved modifiable risk factors, like increased HDL-C and reduced BMI, the reversal of serum metabolic disturbances linked to AD such as an increase in valine levels, and a reduction in systemic inflammation. Leveraging prior clinical studies on AD (n = 1,912), we found that MMKD was inversely associated with the peripheral lipidomic signature of prevalent and incident AD. In the CSF, the MMKD was linked to modified amino acid levels and the breakdown of branched-chain amino acids (BCAAs). Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. In addition, participants with MCI on the MMKD had lower levels of GABA-producing microbes and GABA, and higher levels of GABA-regulating microbes.CONCLUSION: Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.FUNDING: Alzheimer's Gut Microbiome Project, NIA U19AG063744.PMID:39784512 | DOI:10.1002/alz.089878

Alzheimers Dement. 2024 Dec;20 Suppl 2:e088855. doi: 10.1002/alz.088855.ABSTRACTBACKGROUND: Microbiota is modulated by normal aging, but also by Alzheimer's disease (AD) risk factors as poor diet or alteration of sleep patterns. Patients with AD exhibit a dysbiosis characterized by changes in the relative proportions of specific bacterial phyla. Eventually, fecal microbiota transplants (FMT) can improve cognitive deficits and reduce amyloid-ß deposition, at least in mouse models of AD.METHOD: We generated a cohort of AD patients, with control participants matching on age, sex, body mass index, Mini Nutritional Assessment® and education, to sample and compare microbiota composition in the stool and blood compartments. This metagenomic study will be completed by targeted and non-targeted metabolomic analysis to inform about microbiota impact on the host. We precisely evaluated cognition, sleep parameters and dietary habits of the subjects. Moreover, stool samples from 19 patients were pooled by 4, with similar age and sex, from each group, and were transplanted in a mouse model of AD (5XFAD, n = 94) or their control littermates (n = 113) to evaluate the consequences on gut microbiota composition, memory-related behaviors and molecular and cellular biomarkers of AD physiopathology.RESULT: We generated a cohort of well characterized patients representative of mild to moderate AD patients with 45 AD patients [age 75 (SD 0.9), 51% women, minimental state examination (MMSE) 22 (interquartile range, IQR, 17-25)] and 37 controls [age 72 (SD 1.5), 62% women, MMSE 29 (IQR 27-30)]. Our preliminary results indicate i) a potential dysbiosis in AD patients that translates to mouse microbiota composition following FMT. A specific bacterial genus is increased both in 5XFAD and control mice potentially indicating over-representation in AD patients relative to the controls; ii) an impact of microbiota transplanted from AD patients to mouse model on memory and behavior, with an alteration of novel object recognition but also on biomarkers of AD pathology including an increase in mouse Aß1-42 expression level.CONCLUSION: Our results suggest that gut microbiota dysbiosis is associated with AD status and point to a specific bacterial genus. Moreover, FMT from AD patients in an AD mouse model recapitulates important features of the disease, with memory impairment and Aß1-42 accumulations.PMID:39784396 | DOI:10.1002/alz.088855

Alzheimers Dement. 2024 Dec;20 Suppl 2:e088149. doi: 10.1002/alz.088149.ABSTRACTBACKGROUND: Blood-based biomarkers for dementia are gaining attention due to their non-invasive nature and feasibility in regular healthcare settings. Here, we explored the associations between 249 metabolites with all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) and assessed their predictive potential.METHOD: This study included 274,160 participants from the UK Biobank. Cox proportional hazard models were employed to investigate longitudinal associations between metabolites and dementia. The importance of these metabolites was quantified using machine learning algorithms, and a metabolic risk score (MetRS) was subsequently developed for each dementia type. We further investigated how MetRS stratified the risk of dementia onset and assessed its predictive performance, both alone and in combination with demographic and cognitive predictors.RESULT: During a median follow-up of 14.01 years, 5,274 participants developed dementia. Of the 249 metabolites examined, 143 were significantly associated with incident ACD, 130 with AD, and 140 with VaD. Among metabolites significantly associated with dementia, lipoprotein lipid concentrations, linoleic acid, sphingomyelin, glucose, and branched-chain amino acids ranked top in importance. Individuals within the top tertile of MetRS faced a significantly greater risk of developing dementia than those in the lowest tertile. When MetRS was combined with demographic and cognitive predictors, the model yielded the area under the receiver operating characteristic curve (AUC) values of 0.857 for ACD, 0.861 for AD, and 0.873 for VaD.CONCLUSION: We conducted the largest metabolome investigation of dementia to date, for the first time revealed the metabolite importance ranking, and highlighted the contribution of plasma metabolites for dementia prediction.PMID:39784364 | DOI:10.1002/alz.088149

Alzheimers Dement. 2024 Dec;20 Suppl 2:e083975. doi: 10.1002/alz.083975.ABSTRACTBACKGROUND: Disease mechanisms underlying Alzheimer's disease (AD) are heterogenous amongst patients. We recently identified five distinct AD subtypes in cerebrospinal fluid (CSF) proteomic data with data-driven techniques (Figure 1). Two of these subtypes were characterised by brain barrier dysfunction: one with choroid plexus dysfunction, and another with blood-brain barrier dysfunction. Since most lipid transport takes place across these barriers, we compared these two subtypes on CSF lipid levels.METHOD: We included 419 individuals with abnormal amyloid across the clinical spectrum (i.e., AD) and 196 controls with intact cognition and normal AD biomarkers from the Amsterdam Dementia Cohort and related studies with CSF proteomic subtyping available. Next, we performed untargeted complex lipidomics with CSH-QTOF mass spectrometry. Of 3532 lipids detected, 270 could be mapped to known classes. We compared AD barrier subtypes to controls on CSF lipid levels, controlling for sex and age with general linear models.RESULT: Of the 3532 lipids compared to controls, blood-brain barrier dysfunction AD subtype had mostly increased levels of 302 lipids (148 with a known class; Figure 2, all p<0.05), whereas the choroid plexus subtype had mostly decreased levels of 314 lipids (163 known class;, all p<0.05) with an overlap of 150 lipids. These lipids included mostly glycerophospholipids, ceramides, and sphingomyelins. The blood-brain barrier AD subtype further had increased levels of 14 tryglicerides, which were unaltered in the choroid plexus subtype. No specific alterations in CSF levels of known lipid classes were observed for the choroid plexus subtype.CONCLUSION: We previously identified 5 AD subtypes with distinct underlying mechanisms, including two subtypes with involvement of either the blood-brain barrier or the choroid plexus. The subtypes with different type of brain barrier dysfunction had opposite alterations in CSF levels of lipids from specific classes. This implies that these barriers have a distinct role in lipid metabolism and transport alterations in AD, which may require specific treatments.PMID:39784293 | DOI:10.1002/alz.083975

Alzheimers Dement. 2024 Dec;20 Suppl 2:e089899. doi: 10.1002/alz.089899.ABSTRACTBACKGROUND: Metabolomics captures net influences of exposome, diet, gut microbiome, and genome, informing about individuality and how we respond to interventions. Applications of metabolomics in pharmacology are starting to enable a Systems Pharmacology approach, where the outcome of a treatment is considered to evolve from effects on complex molecular networks, enabling insights into response variations. We bring the power of these approaches to the study of the MIND, a Mediterranean DASH diet for prevention of cognitive decline. We evaluate if metabolomics can reveal beneficial metabolic effects linked to improved cognition in all participants or subgroups of individuals.METHODS: Serum samples were collected from participants enrolled in the MIND trial at the Rush University Medical Center site. Participants were randomized to either the MIND diet or control diet group for three years with study visits, cognitive testing, and sample collection occurring at baseline, Years 1, 2, and 3. A total of 746 serum samples from 243 participants were profiled using targeted and non-targeted metabolomics, lipidomics, metagenomics, and foodomics approaches. The longitudinal effects of the diet on the metabolome were evaluated.RESULTS: We identified metabolic signatures of participants on the MIND diet that were unique compared to the control diet. Major changes in lipid metabolism including ceramides, sphingomyelins, PUFAs, and plasmalogens were noted along with changes in energy metabolism and one carbon metabolism (Figure 1). Food components and exposome-related metabolites were changed. For example, tryptophan betaine (lower in cognitive dysfunction) was increased in the MIND diet group with strongest effects in individuals with low levels at baseline. Additionally, glycoprotein acetyls (GlycA, an inflammation marker associated with AD, cognitive decline, reduced brain volume) was decreased in the MIND diet group compared to controls. Detailed mapping of influences on the gut microbiome are being defined and linked to changes in metabolome.CONCLUSION: The metabolomics data highlighted alterations in metabolism in response to MIND diet. These alterations suggest metabolic benefit for cognitive function and inflammation based on big metabolomics data in ADNI and other cohorts. The variation among individuals seen in our analysis warrants stratification of people enrolled in the MIND study before final conclusions are made on its outcome.PMID:39784222 | DOI:10.1002/alz.089899

Alzheimers Dement. 2024 Dec;20 Suppl 2:e092421. doi: 10.1002/alz.092421.ABSTRACTBACKGROUND: Our Alzheimer Disease Metabolomics Consortium (ADMC), part of the Accelerating Medicines Partnership for AD (AMP-AD) and in partnership with AD Neuroimaging Initiative (ADNI), applied state-of-the-art metabolomics and lipidomics technologies combined with genomic and imaging data to map metabolic failures across the trajectory of the disease. Our studies confirmed that peripheral metabolic changes influenced by the exposome inform about cognitive changes, brain imaging changes, and ATN markers for disease confirming that peripheral and central changes are connected, in part through the metabolome.METHODS: To map the biochemical changes in AD, we used various targeted and untargeted metabolic platforms to profile ∼800 postmortem brain tissue, and ∼ 5000 blood samples.RESULTS: Recently, we built a comprehensive reference map of extensive AD-related metabolic changes in brain, spanning multiple AD-related traits, including neuropathological b-amyloid and tau tangle burden, as well as late-life cognitive performance. Using this resource, we extracted novel metabolic including bioenergetic pathways, cholesterol metabolism, neuroinflammation, broad impairment of osmoregulation, an imbalance between excitatory/inhibitory neurotransmitter ratios and identification of tau load as a potential driver of metabolic dysfunction in the AD brain, with minimal contributions from b-amyloid load. As AD and progressive supranuclear palsy (PSP) share the pathological feature of tauopathy and metabolic alterations, we compared their metabolomic profiles to identify shared biological pathways that could be targeted for therapeutic interventions. Our findings indicate that both diseases display oxidative stress, mitochondrial dysfunction, and tau-induced polyamine stress response.CONCLUSION: Overall, through our studies, (1) We identified biochemical processes altered in AD, with findings supported across both metabolomic and proteomic data, indicating multimodal deregulation. (2) Our research pinpointed widespread AD-related biochemical changes across various brain regions with differing levels of neuropathology. While there are many overlapping changes across the brain regions, each region also has its distinct metabolic alterations. (3) We identified biochemical processes disrupted by AD, with parallel findings in other neurodegenerative diseases, hinting at broader implications in neurodegenerative research. Currently, we are working on mapping widespread connections of the brain metabolome with various determinants of AD namely genome, gut microbiome, exposome, and linking with peripheral metabolic alterations in AD.PMID:39784050 | DOI:10.1002/alz.092421

Alzheimers Dement. 2024 Dec;20 Suppl 2:e091167. doi: 10.1002/alz.091167.ABSTRACTBACKGROUND: Alzheimer's disease (AD) pathogenesis is not restricted to amyloid-beta, Aβ, and tau pathologies but involves dysregulation in diverse cellular and molecular processes. Numerous metabolomic studies revealed plasma metabolite alterations in AD individuals compared to healthy controls. Nevertheless, plasma P-tau181, an established biomarker for AD diagnosis and prognosis, has been described to reflect initial multiple cortical region Aβ deposition in cognitively intact adults. The current study aims to identify plasma metabolites associated with plasma P-tau181 at the preclinical stage and better understand the associated biochemical mechanisms for AD pathogenesis.METHOD: In the current study, 100 older adults with no objective cognitive impairment, MoCA and MMSE ≥ 26, from the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort, comprising 65 CI Aβ- (cognitively intact normal brain Aβ) and 35 CI Aβ+ (cognitively intact higher brain Aβ) individuals, were assessed for plasma P-tau181, via ultra-sensitive Quanterix Simoa technology, and plasma metabolites, via mass spectrometry-based BIOCRATES kit, and then investigated for associations, both before and after adjusting for confounding variables, in the study groups. Additionally, P-tau181-associated plasma metabolites were evaluated using the receiver operating characteristic (ROC) curves for the potential to classify brain Aβ status.RESULT: In the entire cohort, significant positive associations of plasma metabolites, including acylcarnitines, amino acid citrulline, and three biogenic amines (creatinine, kynurenine and SDMA), were observed with P-tau181 and similar associations, except for kynurenine, were detected in CI Aβ-. In contrast, in CI Aβ+, only acylcarnitine, AC(10:3), was found to have a positive association with P-tau181 and further, upon including AC(10:3), the AUC for P-tau181 (AUC=70.9%) potentially outperformed (AUC=76.2%), which additionally topped to 83.9% when combined with a base model (Abstract Figure).CONCLUSION: These findings suggest that the higher the plasma P-tau181, the higher the medium chain acylcarnitine, AC(10:3), in plasma in cognitively intact older adults at risk for AD, indicating a link between early Aβ pathology and fatty acid oxidation mediated energy metabolism pathway. Additionally, associated metabolite strengthens the significance of P-tau181 in classifying brain Aβ status in cognitively intact older adults. Therefore, plasma P-tau181-associated plasma metabolite may serve as potential predictive marker for preclinical AD pathogenesis.PMID:39783968 | DOI:10.1002/alz.091167

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095342. doi: 10.1002/alz.095342.ABSTRACTBACKGROUND: Multi-omics integration can clarify molecular mechanisms contributing to Alzheimer's Disease (AD). We conducted a quantitative trait locus (QTL) analysis across three omics layers to identify genetic variants that regulate metabolomics, gene expression, and DNA methylation in AD.METHOD: We analyzed data from Caribbean Hispanic individuals from the Dominican Republic and New York with AD or family history of AD including: N = 750 with whole genome sequencing (WGS), RNA-sequencing, and DNA methylation (in blood), and N = 272 with untargeted metabolomics. Metabolites (N = 5,883) were measured using liquid chromatography coupled to high-resolution mass spectrometry. WGS data (7,588,678 variants) were normalized, aligned, and filtered for quality (BCFTools). Variants with a minor allele frequency greater than 5% were retained. The MatrixEQTL package in R was used for QTL analyses, adjusting for age, sex, and principal components for population substructure. Significant QTLs were declared at a false-discovery rate of 0.05 across all tests. Pathway analyses (clusterProfiler) and colocalization with known AD SNPs were completed to identify causal variants and genes in AD.RESULT: 19,336 SNP-metabolite combinations were statistically significant after adjusting for multiple comparisons (FDR<0.05). 16,421 unique SNPs were identified as QTLs for 60.9% of all metabolites. 68% of FDR-significant metabolomics QTLs overlapped with trans-expression QTLs with P<10-5. The most significant associations were between the metabolomics QTLs (P.FDR<0.05) and cardiovascular pathways including brain ischemia, angiogenesis, and cerebrovascular disease; neuronal pathways including synaptic organization/signaling, neuronal apoptosis, neurogenesis, gliogenesis, and axonogenesis; and AD endophenotypic pathways including cognition, learning and memory, amyloid-beta binding, and dementia. We additionally colocalized SNPs in the Bellenguez et al. 2022 AD GWAS (P<10-3) with metabolomics QTLs (P.FDR<0.05), identifying 24 unique colocalized genes. Notably, SPOCK3 associated with verbal memory (Debette et al., 2015), WWOX associated with Aβ42/Aβ40 ratio (Stevenson-Hoare et al., 2023), and CACNA2D3 associated with an AD subgroup (Mukherjee et al., 2018).CONCLUSION: We identified common genetic variants that regulate metabolite levels, many of which were found to overlap with known AD variants and were enriched in AD-relevant biological pathways. Our next steps include integrating QTLs of transcriptomic and epigenetic data to identify shared molecular pathways that underlie several omics layers leading to AD.PMID:39783736 | DOI:10.1002/alz.095342

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095238. doi: 10.1002/alz.095238.ABSTRACTBACKGROUND: The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with aging and Alzheimer's disease (AD). We have previously shown that TSPO plays a critical role in protective immune responses important in AD. Here we investigated the interaction between TSPO immunomodulatory function and aging in the hippocampus, a region severely affected in AD.METHOD: Using RNAseq, we investigated the role of TSPO in the aging hippocampal transcriptome. Multi-weighted co-expression network analysis (WGCNA) was used to determine the effect of TSPO deletion on aging and identify hub regulators of the molecular network in aging. We compared the TSPO-dependent aging transcriptome signature with drug gene expression signatures in a perturbational signature library called Connectivity Map (CMap). NMR metabolomics was used to determine the effect of TSPO in the context of aging and inflammation on brain metabolites.RESULT: Aging resulted in reversal of inflammatory transcriptional signatures in TSPO-KO hippocampus, with TSPO deletion drastically exacerbating inflammatory transcriptional responses in the aged whilst dampening inflammation in the young hippocampus. This TSPO-aging interaction was linked to transcriptional control of interferon regulatory factors. Drugs such as heat shock protein inhibitors and topoisomerase inhibitors were identified to phenocopy the transcriptional signature characterizing the inflammatory response in TSPO-dependent aging. Through NMR detection, we also noted the exclusive presence of methanediol, another form of formaldehyde, in the aged TSPOKO mice.CONCLUSION: The effect of TSPO in inflammatory responses is age-dependent, an interaction which we linked to transcriptional control of interferon regulatory factors. This TSPO-aging interaction is an important consideration in interpretation TSPO-targeted biomarker and therapeutic studies, as well as in vitro studies which cannot model the aging brain.PMID:39783652 | DOI:10.1002/alz.095238

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095144. doi: 10.1002/alz.095144.ABSTRACTBACKGROUND: High fat diets are a risk factor for Alzheimer Dementia (AD) but little is known about the effect of acute high fat feeding on brain lipid metabolism. Previous studies suggest that diet results may differ by APOE genotype and sex. Here we examined cerebrospinal fluid (CSF) lipidomic profiles after high and low fat feeding in a group of older adults to ascertain how APOE and sex influenced post-prandial lipids.METHOD: As part of the Meal and Memory study (CT# NCT03070535), 78 healthy older adults (50% E4+, each E4 group 56% women) ingested high fat meal (HFM) and low fat meal (LFM) breakfasts 3-5 weeks apart after overnight fast. Plasma triglycerides (TG) were measured at 7 time points, and lumbar puncture was performed 4 hours post-meal. Lipidomics were performed on 250 ul of CSF on a Lipidyzer platform consisting of an AB Sciex 5500 MS/MS QTraps system equipped with a SelexION for differential mobility spectrometry (DMS). Multiple reaction monitoring was used to target 1,530 lipid species (across 20 lipid classes/subclasses) in positive and negative ionization modes with and without DMS, respectively. Lipids were analyzed using MetaboAnalyst 6.0 and SAS OnDemand (2021).RESULT: HFM expectedly increased plasma triglycerides (TG) (LFM peak TG 134±69 mg/dL, HFM peak TG 149±80, F 8.85, p = 0.004), results unaffected by E4 status or sex. No differences were found between the two meals for the 20 lipid classes or for individual lipid species in CSF. When examined by sex*APOE group, important baseline differences were noted in 10 of the 20 lipid classes. Furthermore, there were meal*group effects for phosphoserines (ANOVA F statistic 3.57, p = 0.024), with all groups except for E4+ men showing decreases in these lipids after HFM compared to LFM.CONCLUSION: Meals that produced predictable changes in plasma lipids did not change overall CSF lipids; however, changes were noted when analyzed by APOE*sex and further differed depending on whether the meal was high in fat. These findings suggest that diet or treatments that rely on brain lipid metabolism may need to be further stratified by APOE genotype and sex.PMID:39783594 | DOI:10.1002/alz.095144

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086468. doi: 10.1002/alz.086468.ABSTRACTBACKGROUND: Abnormal glucose metabolism in AD brains correlates with cognitive deficits. The glucose changes are consistent with brain thiamine (vitamin B1) deficiency. In animals, thiamine deficiency causes multiple AD-like changes including memory loss, neuron loss, brain inflammation, enhanced phosphorylation of tau, exaggerated plaque formation and elevated advanced glycation end products (AGE). Increasing thiamine as much as 100 times with the thiamine prodrug benfotiamine diminishes all these changes. These results plus an outstanding safety profile stimulated a double-blind placebo-controlled pilot trial for 12 months with benfotiamine in mild AD patients (MMSE >20). Blood thiamine increased >100 fold compared to placebo. The decline in ADAS cog was diminished by 43% (p<0.125). Worsening of the CDR was 77% lower (p<0.034). Considerable data suggests that the thiamine dependent transketolase regulates AGE, which are elevated in AD. In the pilot trial, the benfotiamine reduced AGE (p<0.044). The following experiments sought to determine if other metabolites/lipids in serum can serve as biomarkers of the effects of benfotiamine.METHOD: Serum from a subset of patients on placebo and benfotiamine groups in the pilot trial was analyzed by LC-MS/MS in parallel for comparative metabolome and lipidome.RESULT: A total of 315 unique metabolites and 417 lipids species were confidently identified and quantified. Differences to benfotiamine treatment were found in 25 metabolites, including thiamine, tyrosine, tryptophan, lysine, and 22 lipid species, especially phosphatidylcholines and triglycerides. Ten of 11 metabolites and 14 of 15 lipid species reported in previous literature to reflect AD progression changed in the opposite direction after benfotiamine treatment. Enrichment pathway analyses show that significantly altered metabolites are involved in glucose metabolism and biosynthesis of aromatic amino acids.CONCLUSION: Benfotiamine reverses the changes of metabolites/lipids reflecting AD progression. Our ongoing NIH funded multicenter trial includes blood biomarkers of thiamine, amyloid, tau, inflammation, neurodegeneration, AGE, and extensive cognitive testing. A larger sample size is necessary to test whether metabolic biomarkers are useful for disease diagnosis, prognosis, and monitoring therapeutic efficacy. This research was partially funded by National Institute of Aging R01AG043679 (G.E.G), AG014930 (G.E.G, S.Z) and R01 AG076634 (GEG, HF, JAL).PMID:39782583 | DOI:10.1002/alz.086468

Alzheimers Dement. 2024 Dec;20 Suppl 6:e090939. doi: 10.1002/alz.090939.ABSTRACTBACKGROUND: Non-human primates (NHP) serve as an important bridge for testing therapeutic agents that have been previously shown to be effective in transgenic mouse models. Our earlier published data using an NHP model of sporadic AD-related pathology that develops abundant cerebral amyloid angiopathy (CAA), squirrel monkeys (SQMs), indicates that chronic treatment with TLR9 agonist, class B CpG ODN, safely ameliorates CAA while promoting cognitive benefits. In the present study, we intended to delineate alterations in brain metabolome induced by chronic CpG ODN administration in order to provide further insight into CpG ODN immunomodulatory capabilities.METHOD: Global metabolomics analysis by HILIC-LC-MS was performed on frontal cortex tissue dissected from geriatric SQMs one month after the final CpG ODN or Vehicle (saline) injection. Tandem spectral (MS2) data was searched against the NIST/METLIN libraries for compound identification. Metabolite peak intensities were used for differential metabolite expression (p<0.05) and pathway analysis was performed using Metaboanalyst 5.0.RESULT: Differential metabolomics analyses revealed 151 putatively identified metabolites that were significantly altered in the brains of CpG ODN-treated SQMs. Amino acids were the largest group of metabolites altered, with decreased levels in the CpG ODN group compared to the saline controls. ROC analyses identified several metabolites strongly associated with CpG ODN treatment, including amino acids such as proline and branched chain amino acids valine, leucine, and isoleucine. Furthermore, trimethylamine N-oxide, a gut microbiome-derived metabolite previously implicated in AD, was the most downregulated metabolite in the brains of CpG ODN monkeys relative to saline controls. Enrichment analysis identified significantly altered pathways including: "Aminoacyl-tRNA biosynthesis", "Valine, leucine and isoleucine biosynthesis", and "Arginine biosynthesis."CONCLUSION: Overall, the brain metabolome in an NHP model of naturally occurring CAA pathology was assessed for the first time. We observed decreased levels of several AD-associated metabolites. These findings further develop our novel concept of immunomodulation in order to provide essential preclinical evidence for CpG ODN use as an effective drug for AD.PMID:39782456 | DOI:10.1002/alz.090939

Int J Biol Sci. 2025 Jan 1;21(2):823-841. doi: 10.7150/ijbs.101055. eCollection 2025.ABSTRACTThe TIRAP protein is an adaptor protein in TLR signaling which links TLR2 and TLR4 to the adaptor protein Myd88. The transcriptomic profiles of zebrafish larvae from a tirap, myd88 and tlr2 mutant and the corresponding wild type controls under unchallenged developmental conditions revealed a specific involvement of tirap in calcium homeostasis and myosin regulation. Metabolomic profiling showed that the tirap mutation results in lower glucose levels, whereas a tlr2 mutation leads to higher glucose levels. A tail-wounding zebrafish larval model was used to identify the role of tirap in leukocyte migration to tissue wounding. We found that more neutrophils were recruited to the wounded region in the tirap mutant larvae compared to the wild type controls, whereas there was no difference in macrophage recruitment. In contrast, published data show that tlr2 and myd88 mutants recruit fewer neutrophils and macrophages to the wounds. Based on cell tracking analysis, we demonstrate that the neutrophil migration speed is increased in the tirap mutant in contrast to neutrophil behavior in myd88 and tlr2 mutants. In conclusion, we show that tirap plays specialized roles distinct from tlr2 and myd88 in signaling, metabolic control, and in regulating neutrophil migration speed upon wounding.PMID:39781449 | PMC:PMC11705633 | DOI:10.7150/ijbs.101055

Clin Epidemiol. 2025 Jan 3;17:1-6. doi: 10.2147/CLEP.S484953. eCollection 2025.NO ABSTRACTPMID:39781206 | PMC:PMC11705965 | DOI:10.2147/CLEP.S484953

JOR Spine. 2025 Jan 8;8(1):e70032. doi: 10.1002/jsp2.70032. eCollection 2025 Mar.ABSTRACTBACKGROUND: Intervertebral disc degeneration disease (IVDD) is a prevalent orthopedic condition that causes chronic lower back pain, imposing a substantial economic burden on patients and society. Despite its high incidence, the pathophysiological mechanisms of IVDD remain incompletely understood.OBJECTIVE: This study aimed to identify metabolomic alterations in IVDD patients and explore the key metabolic pathways and metabolites involved in its pathogenesis.METHODS: Serum samples from 20 IVDD patients and 20 healthy controls were analyzed using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). The identified metabolites were mapped to metabolic pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.RESULTS: Significant alterations were observed in metabolites such as 2-methyl-1,3-cyclohexadiene, stearoyl sphingomyelin, methylcysteine, L-methionine, and cis, cis-muconic acid. These metabolites were involved in pathways including glycine, serine, and threonine metabolism, cyanoamino acid metabolism, and the citrate cycle (TCA cycle).CONCLUSION: The identified metabolic alterations provide insights into the pathogenesis of IVDD and suggest potential therapeutic targets for future investigation.PMID:39781087 | PMC:PMC11707616 | DOI:10.1002/jsp2.70032