TY - JOUR AB - BACKGROUND: Peripheral metabolic health status can reflect and/or contribute to the risk of Alzheimer's disease (AD). Peripheral metabolic health status can be indicated by metabolic health markers, such as inflammatory biomarker glycoprotein acetyls (GlycA) and specific components of lipoproteins (e.g., triacylglycerol of high-density lipoprotein). However, it is unclear if the relationship between peripheral metabolism and AD-related markers is heterogenous among diverse populations and throughout the disease progression. METHODS: Utilizing Alzheimer's Disease Neuroimaging Initiative data, we determined whether baseline plasma GlycA can inform on cognitive and brain structural changes among sub-populations with different diagnosis status. Furthermore, correlation analyses were performed between blood metabolomics and cerebrospinal fluid (CSF) proteomics data in sub-populations with different diagnosis status or different mild cognitive impairment (MCI)/AD outcomes in 3 years. RESULTS: GlycA was elevated in AD patients compared to cognitively normal participants. Baseline GlycA level was associated with executive function decline at 3-9 year follow-up in participants diagnosed with late mild cognitive impairment (LMCI) at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. In addition, peripheral metabolomics signatures of CSF proteomics were well-distinguished between cognitive normal participants and AD patients. Moreover, different peripheral-central metabolic connection was also observed in MCI-AD converters vs. MCI-MCI non-converters across 3 years follow up. CONCLUSION: Peripheral inflammation was linked to future cognitive decline and brain structural atrophy for population at risk. In addition, peripheral metabolomics-CSF proteomics correlation reveals distinguishing peripheral-central connection patterns in AD patients as well as MCI participant soon to develop AD in 3 years. Findings here point to peripheral systemic inflammation and metabolic health in general as risk factors in AD development, pointing to therapeutic intervention related to periphery metabolic health for patients at risk. AU - Liang, N.* AU - Nho, K.* AU - Newman, J.W.* AU - Arnold, M. AU - Huynh, K.* AU - Meikle, P.J.* AU - Borkowski, K.* AU - Kaddurah-Daouk, R.* C1 - 72926 C2 - 56872 TI - Peripheral metabolism informs on future cognitive decline and development of Alzheimer’s disease in population at risk. JO - Alzheimers Dement. VL - 20 PY - 2025 SN - 1552-5260 ER - TY - JOUR AB - INTRODUCTION: In Alzheimer's disease (AD), fibrillar tau gradually progresses from initial seed to larger brain area. However, those brain properties underlying the region-dependent susceptibility to tau accumulation remain unclear. METHODS: We constructed multimodal spatial gradients to characterize molecular properties and connectomic architecture. A predictive model for regional tau deposition was developed by integrating embeddings in the principal gradients of global connectome gradients with gene expression, neurotransmitters, myelin, and amyloid-beta. The model was trained on amyloid-beta-positive participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally validated in independent datasets. RESULTS: The combination of gradients explained up to 77.7% of cross-sectional and 77.3% of longitudinal inter-regional variance of tau deposition. Gene set enrichment analysis of a major gene expression gradient points to synaptic transmission to confer increased susceptibility to tau. DISCUSSION: Our findings reveal a spatially heterogeneous molecular landscape shaping regional susceptibility to tau deposition, presenting a powerful system-level explanatory model of tau pathology in AD. HIGHLIGHTS: Spatial gradients of fundamental molecular brain properties associated with tau pathology. The explanatory power showed high consistency across studies. Genetic analyses suggested that synapse expression plays a vital role in tau accumulation. AU - Luan, Y.* AU - Zheng, L.* AU - Denecke, J.* AU - Dehsarvi, A.* AU - Roemer-Cassiano, S.N.* AU - Dewenter, A.* AU - Steward, A.* AU - Shcherbinin, S.* AU - Svaldi, D.O.* AU - Kotari, V.* AU - Higgins, I.A.* AU - Pontecorvo, M.J.* AU - Valentim, C.* AU - Schnabel, J.A. AU - Casale, F.P. AU - Dyrba, M.* AU - Teipel, S.* AU - Franzmeier, N.* AU - Ewers, M.* C1 - 74363 C2 - 57370 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Multimodal spatial gradients to explain regional susceptibility to fibrillar tau in Alzheimer's disease. JO - Alzheimers Dement. VL - 21 IS - 5 PB - Wiley PY - 2025 SN - 1552-5260 ER - TY - JOUR AB - INTRODUCTION: Adults with Down syndrome (DS) show increased risk for Alzheimer's disease (AD) due to the triplication of chromosome 21 encoding the amyloid precursor protein gene. Further, this triplication possibly contributes to dysregulation of the immune system, furthering AD pathophysiology. METHODS: Using Olink Explore 3072, we measured ∼3000 proteins in plasma from 73 adults with DS and 15 euploid, healthy controls (HC). Analyses for differentially expressed proteins (DEP) were carried out, and pathway and protein network enrichment using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING database was investigated. Within DS, the LASSO (least absolute shrinkage and selection operator) feature selection was applied. RESULTS: We identified 253 DEP between DS and HC and 142 DEP between symptomatic and asymptomatic DS. Several pathways regarding inflammatory and neurodevelopmental processes were dysregulated in both analyses. LASSO feature selection within DS returned 15 proteins as potential blood markers. DISCUSSION: This exploratory proteomic analysis found potential new blood biomarkers for diagnosing DS-AD in need of further investigation. HIGHLIGHTS: Inflammatory pathways are dysregulated in symptomatic versus asymptomatic DS. NFL and GFAP are confirmed as powerful biomarkers in DS with clinical and/or cognitive decline. Further circulating proteins were identified as potential blood biomarkers for symptomatic DS. AU - Wagemann, O.* AU - Nübling, G.* AU - Martínez-Murcia, F.J.* AU - Wlasich, E.* AU - Loosli, S.V.* AU - Sandkühler, K.* AU - Stockbauer, A.* AU - Prix, C.* AU - Katzdobler, S.* AU - Petrera, A. AU - Hauck, S.M. AU - Fortea, J.* AU - Romero-Zaliz, R.* AU - Jiménez-Mesa, C.* AU - Górriz Sáez, J.M.* AU - Höglinger, G.* AU - Levin, J.* C1 - 73726 C2 - 57194 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Exploratory analysis of the proteomic profile in plasma in adults with Down syndrome in the context of Alzheimer's disease. JO - Alzheimers Dement. VL - 21 IS - 3 PB - Wiley PY - 2025 SN - 1552-5260 ER - TY - CONF AB - BACKGROUND: Despite recent breakthroughs, Alzheimer's disease (AD) remains untreatable. In addition, we are still lacking robust biomarkers for early diagnosis and promising novel targets for therapeutic intervention. To enable utilizing the entirety of molecular evidence in the discovery and prioritization of potential novel biomarkers and targets, we have developed the AD Atlas, a network-based multi-omics data integration platform. Through recent extensions, the AD Atlas provides a comprehensive database of high-quality multi-omics data that can be utilized for hypothesis-free ranking of molecular markers and disease modules, as well as prioritization of potential novel targets and drug repositioning candidates. METHOD: We developed several graph-based analysis tools from proximity searches to applications of artificial intelligence that can be applied to the AD Atlas. For prioritization of potential targets and biomarkers, we derived several network-based metrics to score -omics entities for disease relevance by not only assessing evidence for a single marker but also for its functional neighborhood in the AD Atlas network. For disease module identification, we employed graph representation learning coupled with unsupervised clustering to extract functional modules as defined by the network structure. Finally, we propose an ensemble approach that enables weighted aggregation of drug repositioning predictions from both signature-based and network-based algorithms. RESULT: We demonstrate that the AD Atlas enables complex computational analyses for target and biomarker discovery and prioritization as well as in silico drug repositioning in AD. Using the integrated scores for prioritizing single targets and biomarkers for AD, we observe significantly higher relevance scores for genes that have been nominated as promising targets by the AMP-AD consortium. We further find that extracted disease modules are enriched for specific AD-relevant biological domains and can be ranked by disease relevance using similar graph-based metrics. Finally, we demonstrate that drug repositioning candidates are significantly enriched for compounds that were or are being tested in clinical trials for AD. CONCLUSION: High-quality, multi-omics networks, such as the AD Atlas, enable exploitation of large-scale heterogeneous data through computational applications for target, biomarker, disease module, and drug repositioning candidate discovery and prioritization. AU - Arnold, M. C1 - 72927 C2 - 56999 TI - Integrating multi-omics data for target and biomarker discovery. JO - Alzheimers Dement. VL - 20 Suppl 1 PY - 2024 SN - 1552-5260 ER - TY - JOUR AB - BACKGROUND: Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Although metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed. METHODS: We analyzed 342 postmortem brain samples from the Mayo Clinic Brain Bank and examined 658 metabolites in the cerebellar cortex and the temporal cortex between the two tauopathies. RESULTS: Our findings indicate that both diseases display oxidative stress associated with lipid metabolism, mitochondrial dysfunction linked to lysine metabolism, and an indication of tau-induced polyamine stress response. However, specific to AD, we detected glutathione-related neuroinflammation, deregulations of enzymes tied to purines, and cognitive deficits associated with vitamin B. DISCUSSION: Our findings underscore vast alterations in the brain's metabolome, illuminating shared neurodegenerative pathways and disease-specific traits in AD and PSP. HIGHLIGHTS: First high-throughput metabolic comparison of Alzheimer's diesease (AD) versus progressive supranuclear palsy (PSP) in brain tissue. Cerebellar cortex (CER) shows substantial AD-related metabolic changes, despite limited proteinopathy. AD impacts both CER and temporal cortex (TCX); PSP's changes are primarily in CER. AD and PSP share metabolic alterations despite major pathological differences. AU - Batra, R.* AU - Krumsiek, J.* AU - Wang, X.* AU - Allen, M.* AU - Blach, C.* AU - Kastenmüller, G. AU - Arnold, M. AU - Ertekin-Taner, N.* AU - Kaddurah-Daouk, R.* C1 - 72128 C2 - 56504 TI - Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy. JO - Alzheimers Dement. PY - 2024 SN - 1552-5260 ER - TY - CONF AB - BACKGROUND: 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. AU - Batra, R.* AU - Arnold, M. AU - Wang, X.* AU - Allen, M.* AU - Wörheide, M. AU - Blach, C.* AU - Levey, A.I.* AU - Seyfried, N.T.* AU - Bennett, D.A.* AU - Kastenmüller, G. AU - Ertekin-Taner, N.* AU - Kaddurah-Daouk, R.* AU - Krumsiek, J.* C1 - 72988 C2 - 57001 TI - Central and Peripheral Biochemical Changes in Alzheimer’sDisease: Insights from the Alzheimer Disease MetabolomicsConsortium. JO - Alzheimers Dement. VL - 20 Suppl 2 PY - 2024 SN - 1552-5260 ER - TY - CONF AB - BACKGROUND: Alzheimer's disease (AD) is a devastating form of dementia, and its prevalence is rising as human lifespan increases. Our lab created the AD-BXD mouse model, which expresses AD mutations across a genetically diverse reference panel (BXD), to identify factors that confer resilience to cognitive decline in AD. This model mimics key characteristics of human AD including variation in age of onset and severity of cognitive decline. METHOD: To facilitate discovery of conserved mechanisms of resilience to AD, we generated a cross-species single-nuclei transcriptomic dataset from normal and AD human (ROSMAP) and AD-BXD mouse frontal cortex tissue. We interrogated resilience-associated gene expression signatures, validated resilience candidate genes with human reference data, and used a druggability ranking and drug repositioning pipeline to nominate drugs to promote resilience to AD. To learn more about the context of resilience gene expression, we used a hierarchical mapping algorithm to predict anatomical locations of cells expressing resilience gene signatures. RESULT: We found the strongest gene expression signature associated with cognitive resilience to AD arises from excitatory layer 4/5 (eL4/5) cortical intratelencephalic neurons. This resilience signature includes genes involved in synaptic plasticity, vesicle transport, and axonal and dendritic development. We found that 27 of the 61 genes in the resilience signature are druggable and identified several candidate drugs for further investigation (Telpoukhovskaia et al., 2022). We also identified genes expressed across a continuum of cognitive performance. Our hierarchical mapping approach showed that the eL4/5 neurons expressing resilience signature genes are distributed throughout the frontal cortex, mainly in the somatomotor area. CONCLUSION: We identified 61 candidate resilience genes to target with new or existing drugs. We also determined that expression of resilience candidate genes occurs in eL4/5 neurons in the somatomotor region of the cortex. Ongoing projects in the lab aim to evaluate efficacy of nominated drugs and profile learning-specific proteomes of eL4/5 neurons in resilient and susceptible AD-BXD strains. When integrated with existing genetic, behavioral, and pathological data, our work will elucidate the cellular, molecular, and genetic mechanisms that contribute to cognitive resilience in face of neurodegenerative disease pathology. AU - Fish, L.A.* AU - Telpoukhovskaia, M.A.* AU - Algoo, J.* AU - Hadad, N.* AU - Gurdon, B.* AU - Dai, M.* AU - Ouellette, A.R.* AU - Neuner, S.M.* AU - Dunn, A.R.* AU - Willcox, J.A.L.* AU - Wu, Y.* AU - Dumitrescu, L.C.* AU - Bellur, O. AU - Zhang, J.* AU - O'Connell, K.M.S.* AU - Dammer, E.B.* AU - Seyfried, N.T.* AU - Muzumdar, S.* AU - Gillis, J.* AU - Robson, P.J.* AU - Arnold, M. AU - Hohman, T.J.* AU - Philip, V.M.* AU - Menon, V.* AU - Kaczorowski, C.C.* C1 - 72989 C2 - 57000 TI - A cognitive resilience gene expression signature in excitatory intratelencephalic cortical neurons. JO - Alzheimers Dement. VL - 20 Suppl 8 PY - 2024 SN - 1552-5260 ER - TY - JOUR AB - INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy. AU - Hüper, L.* AU - Steinacker, P.* AU - Polyakova, M.* AU - Mueller, K.* AU - Godulla, J.* AU - Herzig, S.* AU - Danek, A.* AU - Engel, A.* AU - Diehl-Schmid, J.* AU - Classen, J.* AU - Fassbender, K.* AU - Fliessbach, K.* AU - Jahn, H.* AU - Kassubek, J.* AU - Kornhuber, J.* AU - Landwehrmeyer, B.* AU - Lauer, M.* AU - Obrig, H.* AU - Oeckl, P.* AU - Prudlo, J.* AU - Saur, D.* AU - Anderl-Straub, S.* AU - Synofzik, M.* AU - Wagner, M. AU - Wiltfang, J.* AU - Winkelmann, J. AU - Volk, A.E.* AU - Huppertz, H.J.* AU - Otto, M.* AU - Schroeter, M.L.* C1 - 70824 C2 - 55756 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Neurofilaments and progranulin are related to atrophy in frontotemporal lobar degeneration - A transdiagnostic study cross-validating atrophy and fluid biomarkers. JO - Alzheimers Dement. PB - Wiley PY - 2024 SN - 1552-5260 ER - TY - CONF AB - BACKGROUND: 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. AU - MahmoudianDehkordi, S.* AU - Voigt-Zuwala, R.M.* AU - Dhana, K.* AU - Labus, J.S.* AU - Mohanty, I.* AU - Agarwal, P.* AU - Morris, M.C.* AU - Barnes, L.L.* AU - Sacks, F.* AU - Batra, R.* AU - Kastenmüller, G. AU - Keshavarzian, A.* AU - Kaddurah-Daouk, R.* C1 - 72987 C2 - 57002 TI - Metabolomics Analysis of the MIND Study Informs about Metabolic Benefit and Heterogeneity among Individuals‐ A Precision Medicine Approach for Diet Interventions. JO - Alzheimers Dement. VL - 20 Suppl 2 PY - 2024 SN - 1552-5260 ER - TY - JOUR AB - INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation. METHODS: We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age. RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. DISCUSSION: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD. HIGHLIGHTS: This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease. Mouse models exhibit broad sex-specific metabolic differences, similar to human study cohorts. The early-onset 5XFAD mouse model primarily alters brain metabolites while the late-onset LOAD1 model primarily changes serum metabolites. Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum. AU - Pandey, R.S.* AU - Arnold, M. AU - Batra, R.* AU - Krumsiek, J.* AU - Kotredes, K.P.* AU - Garceau, D.* AU - Williams, H.* AU - Sasner, M.* AU - Howell, G.R.* AU - Kaddurah-Daouk, R.* AU - Carter, G.W.* C1 - 70549 C2 - 55512 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Metabolomics profiling reveals distinct, sex-specific signatures in serum and brain metabolomes in mouse models of Alzheimer's disease. JO - Alzheimers Dement. PB - Wiley PY - 2024 SN - 1552-5260 ER - TY - CONF AB - BACKGROUND: 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. AU - Schweickart, A.* AU - Huynh, K.* AU - Batra, R.* AU - Neth, B.J.* AU - Martino, C.* AU - Dilmore, A.H.* AU - Giles, C.* AU - Wang, T.* AU - Mellett, N.A.* AU - Duong, T.* AU - Shenhav, L.* AU - Zhang, A.* AU - Shi, P.* AU - Karu, N.* AU - West, K.* AU - Zemlin, J.* AU - Rahman, G.* AU - Panitchpakdi, M.* AU - Meehan, M.* AU - Weldon, K.C.* AU - Register, T.C.* AU - Arnold, M. AU - Meikle, P.J.* AU - Schimmel, L.* AU - Blennow, K.* AU - Zetterberg, H.* AU - Blach, C.* AU - Dorrestein, P.* AU - Knight, R.* AU - Krumsiek, J.* AU - Kaddurah-Daouk, R.* AU - Craft, S.* C1 - 72986 C2 - 57003 TI - A Modified Mediterranean Ketogenic Diet reverses signaturesand mitigates modifiable risk factors of Alzheimer’s disease. JO - Alzheimers Dement. VL - 20 Suppl 7 PY - 2024 SN - 1552-5260 ER - TY - JOUR AB - INTRODUCTION: In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the Alzheimer's disease and related dementias (ADRD) field. METHODS: During the workshop, the participants brainstormed new directions to overcome current barriers to providing patients with effective ADRD therapeutics. The participants outlined specific areas of focus. Following the workshop, each group used standard literature search methods to provide background for each topic. RESULTS: The team of invited experts identified four key areas that can be collectively addressed to make a significant impact in the field: (1) Prioritize the diversification of disease targets, (2) enhance factors promoting resilience, (3) de-risk clinical pipeline, and (4) centralize data management. DISCUSSION: In this report, we review these four objectives and propose innovations to expedite ADRD therapeutic pipelines. AU - Telpoukhovskaia, M.A.* AU - Murdy, T.J.* AU - Marola, O.J.* AU - Charland, K.* AU - MacLean, M.* AU - Luquez, T.* AU - Lish, A.M.* AU - Neuner, S.* AU - Dunn, A.* AU - Onos, K.D.* AU - Wiley, J.* AU - Archer, D.* AU - Huentelman, M.J.* AU - Arnold, M. AU - Menon, V.* AU - Goate, A.* AU - Van Eldik, L.J.* AU - Territo, P.R.* AU - Howell, G.R.* AU - Carter, G.W.* AU - O'Connell, K.M.S.* AU - Kaczorowski, C.C.* C1 - 70264 C2 - 55477 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - New directions for Alzheimer's disease research from the Jackson Laboratory Center for Alzheimer's and Dementia Research 2022 workshop. JO - Alzheimers Dement. VL - 10 IS - 1 PB - Wiley PY - 2024 SN - 1552-5260 ER - TY - CONF AB - Impaired glucose uptake in the brain is one of the earliest presymptomatic manifestations of Alzheimer's disease (AD). The absence of symptoms for extended periods of time suggests that compensatory metabolic mechanisms can provide resilience. Here, we introduce the concept of a systemic 'bioenergetic capacity' as the innate ability to maintain energy homeostasis under pathological conditions, potentially serving as such a compensatory mechanism. We argue that fasting blood acylcarnitine profiles provide an approximate peripheral measure for this capacity that mirrors bioenergetic dysregulation in the brain. Using unsupervised subgroup identification, we show that fasting serum acylcarnitine profiles of participants from the AD Neuroimaging Initiative yields bioenergetically distinct subgroups with significant differences in AD biomarker profiles and cognitive function. To assess the potential clinical relevance of this finding, we examined factors that may offer diagnostic and therapeutic opportunities. First, we identified a genotype affecting the bioenergetic capacity which was linked to succinylcarnitine metabolism and significantly modulated the rate of future cognitive decline. Second, a potentially modifiable influence of beta-oxidation efficiency seemed to decelerate bioenergetic aging and disease progression. Our findings, which are supported by data from more than 9,000 individuals, suggest that interventions tailored to enhance energetic health and to slow bioenergetic aging could mitigate the risk of symptomatic AD, especially in individuals with specific mitochondrial genotypes. AU - Arnold, M. AU - Buyukozkan, M.* AU - Doraiswamy, P.M.* AU - Nho, K.* AU - Wu, T. AU - Gudnason, V.* AU - Launer, L.J.* AU - Wang-Sattler, R. AU - Adamski, J. AU - de Jager, P.L.* AU - Ertekin-Taner, N.* AU - Bennett, D.A.* AU - Saykin, A.J.* AU - Peters, A. AU - Suhre, K.* AU - Kaddurah-Daouk, R.* AU - Kastenmüller, G. AU - Krumsiek, J.* C1 - 71982 C2 - 56292 TI - Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease. JO - Alzheimers Dement. VL - 19 PY - 2023 SN - 1552-5260 ER - TY - JOUR AB - INTRODUCTION: Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in the brain has been missing. METHODS: We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures. RESULTS: We observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation, and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than amyloid beta pathology. DISCUSSION: This work provides a comprehensive reference map of metabolic brain changes in AD that lays the foundation for future mechanistic follow-up studies. AU - Batra, R.* AU - Arnold, M. AU - Wörheide, M. AU - Allen, M.* AU - Wang, X.* AU - Blach, C.* AU - Levey, A.I.* AU - Seyfried, N.T.* AU - Ertekin-Taner, N.* AU - Bennett, D.A.* AU - Kastenmüller, G. AU - Kaddurah-Daouk, R.F.* AU - Krumsiek, J.* C1 - 65635 C2 - 52756 TI - The landscape of metabolic brain alterations in Alzheimer's disease. JO - Alzheimers Dement. PY - 2022 SN - 1552-5260 ER - TY - JOUR AB - Background: Alterations in the brain-gut microbiome system are thought to play an important role in the development of neurodegenerative diseases. While the great majority of secreted primary bile acids (BAs) are reabsorbed in the ileum, about 5% are metabolized by gut microbes and reabsorbed. Alterations in secondary BAs metabolism associated with specific gut-microbial species, and reflected in altered ratios of primary and secondary BAs have recently been linked with brain atrophy and cognitive decline. The aim of this study was to investigate whether interactions between brain-derived morphometric phenotypes and BA profiles can predict baseline cognitive status (cognitively normal (CN), mild cognitive impairment (MCI), Dementia (AD)) or conversion status (MCI to AD). Method: The sample included 1013 CN, MCI, and AD participants from the Alzheimer’s Disease Neuroimaging Initiative cohort. Regional brain morphometry was derived using Freesurfer v5.1 and Desikan-Killany atlas. Targeted metabolomics profiling quantifed concentrations of 20 BAs from serum samples. Analysis was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO). Data was split into a training and test sets (70/30 split) to determine predictive accuracy. Result: A correlated brain and BA ratio signature predicted cognitive status (CN vs AD) with high predictive accuracy (see Figure 1). The brain signature of AD, compared to CN was characterized by gray matter atrophy in a limited number of regions including the hippocampus, entorhinal cortex, amygdala and medial temporal regions. The BA ratio signature was characterized by higher ratio of glycolithocholic acid and glycodeoxycholic acid to ursodeoxycholic acid, GLCA:UDCA, GDCA:UDCA along with a lower ratio of cholic acid to GLCA in AD. Predicted conversion from MCI to AD at 2 and 4 years had lower predictive accuracy (BER∼ = 34%). Conclusion: These findings demonstrate that interactions between brain signatures and secondary BA profiles predict baseline cognitive status with high accuracy. They support the concept that differences in gut microbial metabolism of certain BAs, possibly related to diet, play a role in shaping the brain signature in AD patients. Compared to previously employed univariate approaches, the supervised multi-omics multivariate integration approach complements and elucidates the interactions along the brain gut microbiome axis that contribute to AD. AU - Labus, J.S.* AU - Liu, C.* AU - Blach, C.* AU - Arnold, M. AU - Kaddurah-Daouk, R.F.* AU - Mayer, E.A.* C1 - 67078 C2 - 53450 TI - Interactions between brain and bile acid ratio profiles predict baseline cognitive status. JO - Alzheimers Dement. VL - 18 IS - S4 PY - 2022 SN - 1552-5260 ER - TY - JOUR AB - Background: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). Methods: We provide a detailed comparison of serum beta-synuclein immunoprecipitation – mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. Results: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. Discussion: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. Highlights: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL). AU - Oeckl, P.* AU - Anderl-Straub, S.* AU - Danek, A.* AU - Diehl-Schmid, J.* AU - Fassbender, K.* AU - Fliessbach, K.* AU - Halbgebauer, S.* AU - Huppertz, H.J.* AU - Jahn, H.* AU - Kassubek, J.* AU - Kornhuber, J.* AU - Landwehrmeyer, B.* AU - Lauer, M.* AU - Prudlo, J.* AU - Schneider, A.* AU - Schroeter, M.L.* AU - Steinacker, P.* AU - Volk, A.E.* AU - Wagner, M. AU - Winkelmann, J. AU - Wiltfang, J.* AU - Ludolph, A.C.* AU - Otto, M.* C1 - 66263 C2 - 52765 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 1358-1371 TI - Relationship of serum beta-synuclein with blood biomarkers and brain atrophy. JO - Alzheimers Dement. VL - 19 IS - 4 PB - Wiley PY - 2022 SN - 1552-5260 ER - TY - JOUR AB - Background: The pathogenesis of dementia and depression is complex involving the interplay of genetic and environmental risk factors including diet, life-style and the gut microbiome. Dementia and depression co-occur and metabolomics studies may shed light on the interplay of the various risk factors. Methods: We have studied the metabolome of 118,466 individuals including 8462 cases with a history of major depression (MDD) and 1,364 patients who developed dementia during follow-up from the UK Biobank (UKB). The human metabolome was profiled using the Nightingale platform. Result: For both disorders, we find direct evidence that metabolites involved in the tricarboxylic acid (TCA) cycle are altered in patients, albeit that different metabolites emerge as the most significant drivers in the two disorders. Both dementia and MDD dementia patients show a marked change in the HDL/VLDL axis in blood, with similar changes in particular small and extra large HDL subfractions seen in patients with MDD and those who develop depression in the future. The two patients groups further show similar changes in fat metabolism as measured by omega 3, omega 6 and PUFA levels. When comparing metabolic profiles over environmental risk factors for MDD and dementia, we find that MDD clusters with dementia risk factors physical activity, history of previous smoking and social isolation. Integrating the metabolic profiles of major depression and the gut microbiome we find that the gut microbiome may be a key mediator in the relationship between various metabolites involved in the HDL subfractions associated to both MDD and dementia. Conclusion: Our study shows that energy and fat metabolism is disturbed in patients with MDD as well as patients who develop dementia in the future and that the interplay between the genome, exposome, gut microbiome, human metabolome may play role in the co-occurrence of major depression and dementia. AU - van Duijn, C.M.* AU - Amin, N.* AU - Liu, J.* AU - Bonnechere, B.* AU - MahmoudianDehkordi, S.* AU - Arnold, M.* AU - Batra, R.* AU - Chiou, Y.J.* AU - Fernandes, M.C.* AU - Ikram, M.A.* AU - Kraaij, R.* AU - Krumsiek, J.* AU - Newby, D.* AU - Nho, K.* AU - Radjabzadeh, D.* AU - Saykin, A.J.* AU - Shi, L.* AU - Sproviero, W.* AU - Winchester, L.M.* AU - Yang, Y.* AU - Nevado-Holgado, A.J.* AU - Kastenmüller, G. AU - Kaddurah-Daouk, R.* C1 - 67072 C2 - 53446 TI - Interplay of the human exposome, metabolome and gut microbiome in dementia and major depression. JO - Alzheimers Dement. VL - 18 IS - S4 PY - 2022 SN - 1552-5260 ER - TY - JOUR AB - Introduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target. AU - Wang, T.* AU - Huynh, K.* AU - Giles, C.* AU - Mellett, N.A.* AU - Duong, T.* AU - Nguyen, A.* AU - Lim, W.L.F.* AU - Smith, A.A.T.* AU - Olshansky, G.* AU - Cadby, G.* AU - Hung, J.* AU - Hui, J.* AU - Beilby, J.* AU - Watts, G.F.* AU - Chatterjee, P.* AU - Martins, I.* AU - Laws, S.M.* AU - Bush, A.I.* AU - Rowe, C.C.* AU - Villemagne, V.L.* AU - Ames, D.* AU - Masters, C.L.* AU - Taddei, K.* AU - Doré, V.* AU - Fripp, J.* AU - Arnold, M. AU - Kastenmüller, G. AU - Nho, K.* AU - Saykin, A.J.* AU - Baillie, R.* AU - Han, X.* AU - Martins, R.N.* AU - Moses, E.K.* AU - Kaddurah-Daouk, R.* AU - Meikle, P.J.* C1 - 64197 C2 - 51801 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 2151-2166 TI - APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies. JO - Alzheimers Dement. VL - 18 IS - 11 PB - Wiley PY - 2022 SN - 1552-5260 ER - TY - JOUR AB - BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder for which there currently are no disease-modifying treatments available. To accelerate the path to effective intervention strategies, drug repositioning - the application of available compounds in a novel disease context - has gained increasing attention as a promising alternative to de novo drug development. Rich multi-omics data, generated by large international and interdisciplinary AD consortia, is now enabling the implementation of novel methods that have the potential to drive the computational identification and prioritization of promising repositioning candidates. METHOD: We recently developed the AD atlas, a web-based multi-omics resource that integrates multiple layers of heterogenous data from different studies and cohorts, including omics QTLs, transcriptomic, proteomic and metabolomic correlation networks, as well as genetic and multi-omics associations with AD and associated biomarkers/endophenotypes. Using this atlas, we generated and analyzed molecular context networks surrounding AD-associated genes as well as those targeted by drug repositioning candidates proposed in the literature. Subsequent enrichment analysis on AD subnetworks was used to identify drugs with overlapping molecular signatures on the gene expression level, while target networks of repositioning candidates were investigated for their potential involvement in AD pathogenesis. RESULT: We found ample evidence for the potential of integrative multi-omics approaches for drug repositioning in AD. For instance, enrichment analysis of the context network surrounding the AD-associated genes APOE and CLU identified multiple repositioning candidates, where the top hits were drugs that were either previously proposed as promising or already subjected to clinical trials, such as fluoxetine, rosiglitazone, and valproate. Investigating candidate drugs, the exploration of the context network targeted by statins revealed functional links to TYROBP/TREM2 signaling, suggesting a potential protective effect of this drug class through modulation of neuroinflammatory pathways. CONCLUSION: Our results highlight multiple opportunities to advance drug repositioning efforts in AD by integrative analysis of comprehensive multi-omics data. Automation of our analyses using network-based machine learning approaches and extension of the AD atlas with multi-omics data from drug screens to resolve directionalities will allow us to globally identify molecular pathways disturbed in AD that are targetable by drug repositioning candidates. AU - Wörheide, M. AU - Krumsiek, J.* AU - Kastenmüller, G. AU - Kaddurah-Daouk, R.F.* AU - Arnold, M. C1 - 64278 C2 - 51835 TI - A proof of concept study towards multi-omics-based computational drug repositioning in Alzheimer's disease. JO - Alzheimers Dement. VL - 17 PY - 2022 SN - 1552-5260 ER - TY - JOUR AB - BACKGROUND: L-carnitine is present in the mammalian cells as free carnitine (FC) and acylcarnitine and the adult human brain contains almost 10% of long chain acylcarnitine. Acylcarnitines are functionally involved in β-oxidation of fatty acids and are also known for their role in neuroprotection. Levels of plasma acylcarnitines are known to decreased on aging. It is important to understand the association of acylcarnitines with cognitive impairment in Alzheimer's disease (AD). METHOD: We integrated the transcriptome data from 1000 post-mortem brain samples from ROS/MAP, Mayo clinic and Mount Sinai Brain bank cohort with the brain region-specific metabolic networks. We calculated the metabolic fluxes for the reactions in the model and identified those that showed differential fluxes in AD samples. We filtered the reactions that are involved in acylcarnitine synthesis and transport namely carnitine transport, fatty acid oxidation, citric acid cycle, and glutathione metabolism. RESULT: We found differences in metabolic fluxes for reactions involved in the acetylcarnitine transport to mitochondria (ACRNtm), carnitine palmitoyl transferase 1 and 2 (CPT1 and CPT2) as well as acyl-CoA dehydrogenase short and medium chain (ACADS, ACADM) located in mitochondria in AD samples. Using gene-based association analysis in participants of the AD Neuroimaging Initiative (ADNI) phases 1, GO and 2, we identified genetic variants linked to CPT1, CPT2, ACADM and ACADS genes suggested from the metabolic flux analysis. CONCLUSION: Our findings suggest that acylcarnitine synthesis and transport is altered in AD. Altered metabolism of short and medium chain acylcarnitines can be used as metabolic features of AD. AU - Baloni, P.* AU - Nho, K.* AU - Arnold, M. AU - Louie, G.* AU - Kueider-Paisley, A.* AU - Saykin, A.J.* AU - Ekroos, K.* AU - Funk, C.* AU - Hood, L.* AU - Price, N.D.* AU - Baillie, R.* AU - Kastenmüller, G. AU - Han, X.* AU - Kaddurah-Daouk, R.F.* C1 - 64282 C2 - 51834 TI - Investigating the importance of acylcarnitines in Alzheimer's disease. JO - Alzheimers Dement. VL - 17 PY - 2021 SN - 1552-5260 ER - TY - JOUR AB - Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids and medium/long-chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co-expression network analysis of the AMP-AD brain RNA-seq data suggests the CPT1A- and ABCA1-centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short-chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large-scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis. AU - Horgusluoglu, E.* AU - Neff, R.* AU - Song, W.M.* AU - Wang, M.* AU - Wang, Q.* AU - Arnold, M. AU - Krumsiek, J.* AU - Galindo-Prieto, B.* AU - Ming, C.* AU - Nho, K.* AU - Kastenmüller, G. AU - Han, X.* AU - Baillie, R.* AU - Zeng, Q.* AU - Andrews, S.* AU - Cheng, H.* AU - Hao, K.* AU - Goate, A.* AU - Bennett, D.A.* AU - Saykin, A.J.* AU - Kaddurah-Daouk, R.* AU - Zhang, B.* C1 - 63499 C2 - 51437 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease. JO - Alzheimers Dement. PB - Wiley PY - 2021 SN - 1552-5260 ER - TY - JOUR AB - Introduction: Tau, a natively unfolded soluble protein, forms abnormal oligomers and insoluble filaments in several neurodegenerative diseases, including Alzheimer disease (AD). Tau-induced toxicity is mainly due to oligomers rather than monomers or fibrils. Methods: We have developed monoclonal antibodies against purified low-n tau oligomers of the tau repeat domain as a tool to neutralize tau aggregation and toxicity. In vitro aggregation inhibition was tested by thioflavin S, dynamic light scattering (DLS), and atomic force microscopy (AFM). Using a split-luciferase complementation assay and fluorescence-activated cell sorting (FACS), the inhibition of aggregation was analyzed in an N2a cell model of tauopathy. Results: Antibodies inhibited tau aggregation in vitro up to ~90% by blocking tau at an oligomeric state. Some antibodies were able to block tau dimerization/oligomerization in cells, as measured by a split-luciferase complementation assay. Antibodies applied extracellularly were internalized and led to sequestration of tau into lysosomes for degradation. Discussion: Novel low-n tau oligomer specific monoclonal antibody inhibits Tau oligomerization in cells and promotes toxic tau clearance. AU - Chandupatla, R.R.* AU - Flatley, A. AU - Feederle, R. AU - Mandelkow, E.M.* AU - Kaniyappan, S.* C1 - 60541 C2 - 49357 TI - Novel antibody against low-n oligomers of tau protein promotes clearance of tau in cells via lysosomes. JO - Alzheimers Dement. VL - 6 IS - 1 PY - 2020 SN - 1552-5260 ER - TY - JOUR AB - Introduction: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging-related declines in circulating plasmalogens containing omega-3 fatty acids may increase AD risk by reducing plasmalogen availability.Methods: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neu-roimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (U Penn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL-PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index). We tested associations with baseline diagnosis, cognition, and cere-brospinal fluid (CSF) AD biomarkers.Results: Results revealed statistically significant negative relationships in ADNI between AD versus CN with PL-PX (P = 0.007) and PBV (P = 0.005), late mild cognitive impairment (LMCI) versus cognitively normal (CN) with PL-PX (P = 2.89 x 10(-5)) and PBV (P = 1.99 x 10(-4), and AD versus LMCI with POPE (P = 1.85 x 10(-4)). In the UPenn cohort, AD versus CN diagnosis associated negatively with PL/PE (P = 0.0191) and PBV (P = 0.0296).In ADNI, cognition was negatively associated with plasmalogen indices, including Alzheimer's Disease Assessment Scale 13-item cognitive subscale (ADAS-Cog13; PL-PX: P = 3.24 x 10(-6); PBV: P = 6.92 x 10(-5)) and Mini-Mental State Examination (MMSE; PL-PX: P = 1.28 x 10(-9); PBV: P = 6.50 x 10(-9)). In the UPenn cohort, there was a trend toward a similar relationship of MMSE with PL/PE (P = 0.0949).In ADN I, CSF total-tau was negatively associated with PL-PX (P = 5.55 x 10(-6)) and PBV (P = 7.77 x 10(-6)). Additionally, CSF t-tau/A beta(1-42) 42 ratio was negatively associated with these same indices (PL-PX, P= 2.73 x 10(-6); PBV, P = 4.39 x 10(-6)). In the UPenn cohort, PL/PE was negatively associated with CSF total-tau (P = 0.031) and t-tau/A beta(1-42) (P = 0.021). CSF A beta(1-42) was not significantly associated with any of these indices in either cohort.Discussion: These data extend previous studies by showing an association of decreased plasmalogen indices with AD, mild cognitive impairment (MCI), cognition, and CSF tau. Future studies are needed to better define mechanistic relationships, and to test the effects of interventions designed to replete serum plasmalogens. AU - Kling, M.A.* AU - Goodenowe, D.B.* AU - Senanayake, V.* AU - MahmoudianDehkordi, S.* AU - Arnold, M. AU - Massaro, T.J.* AU - Baillie, R.* AU - Han, X.* AU - Leung, Y.Y.* AU - Saykin, A.J.* AU - Nho, K.* AU - Kueider-Paisley, A.* AU - Tenenbaum, J.D.* AU - Wang, L.S.* AU - Shaw, L.M.* AU - Trojanowski, J.Q.* AU - Kaddurah-Daouk, R.F.* C1 - 59775 C2 - 48985 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 1234-1247 TI - Circulating ethanolamine plasmalogen indices in Alzheimer's disease: Relation to diagnosis, cognition, and CSF tau. JO - Alzheimers Dement. VL - 16 IS - 9 PB - Wiley PY - 2020 SN - 1552-5260 ER - TY - JOUR AB - Introduction: Comorbidity with metabolic diseases indicates that lipid metabolism plays a role in the etiology of Alzheimer's disease (AD). Comprehensive lipidomic analysis can provide new insights into the altered lipid metabolism in AD. Method: In this study, a total 349 serum lipids were measured in 806 participants enrolled in the Alzheimer's Disease Neuroimaging Initiative Phase 1 cohort and analyzed using lipid-set enrichment statistics, a data mining method to find coregulated lipid sets. Results: We found that sets of blood lipids were associated with current AD biomarkers and with AD clinical symptoms. AD diagnosis was associated with 7 of 28 lipid sets of which four also correlated with cognitive decline, including polyunsaturated fatty acids. Cerebrospinal fluid amyloid beta (Aβ1-42) correlated with glucosylceramides, lysophosphatidylcholines and unsaturated triacylglycerides; cerebrospinal fluid total tau and brain atrophy correlated with monounsaturated sphingomyelins and ceramides, in addition to EPA-containing lipids. Discussion: AD-associated lipid sets indicated that lipid desaturation, elongation, and acyl chain remodeling processes are disturbed in AD subjects. Monounsaturated lipid metabolism was important in early stages of AD, whereas the polyunsaturated lipid metabolism was associated with later stages of AD. Our study provides several new hypotheses for studying the role of lipid metabolism in AD. AU - Barupal, D.K.* AU - Baillie, R.* AU - Fan, S.* AU - Saykin, A.J.* AU - Meikle, P.J.* AU - Arnold, M. AU - Nho, K.* AU - Fiehn, O.* AU - Kaddurah-Daouk, R.* AU - Alzheimer's Disease Neuroimaging Initiative* AU - Alzheimer Disease Metabolomics Consortium* C1 - 56881 C2 - 47303 SP - 619-627 TI - Sets of coregulated serum lipids are associated with Alzheimer's disease pathophysiology. JO - Alzheimers Dement. VL - 11 PY - 2019 SN - 1552-5260 ER - TY - JOUR AB - Introduction: Bile 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 Alzheimer's disease (AD) including neuroinflammation and amyloid-beta deposition.Method: Serum 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: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([F-18]FDG PET).Results: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSFA beta(1-42) ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05).Discussion: This 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. (C) 2018 Published by Elsevier Inc. on behalf of the Alzheimer's Association. AU - Nho, K.* AU - Kueider-Paisley, A.* AU - MahmoudianDehkordi, S.* AU - Arnold, M. AU - Risacher, S.L.* AU - Louie, G.* AU - Blach, C.* AU - Baillie, R.A.* AU - Han, X.* AU - Kastenmüller, G. AU - Jia, W.* AU - Xie, G.* AU - Ahmad, S.* AU - Hankemeier, T.* AU - van Duijn, C.M.* AU - Trojanowski, J.Q.* AU - Shaw, L.M.* AU - Weiner, M.W.* AU - Doraiswamy, P.M.* AU - Saykin, A.J.* AU - Kaddurah-Daouk, R.* C1 - 54551 C2 - 45666 CY - 360 Park Ave South, New York, Ny 10010-1710 Usa SP - 232-244 TI - Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers. JO - Alzheimers Dement. VL - 15 IS - 2 PB - Elsevier Science Inc PY - 2019 SN - 1552-5260 ER - TY - JOUR AB - Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), 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's disease (AD).Methods: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, 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 confounders and multiple testing.Results: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid: CA, which reflects 7 alpha-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.Discussion: We 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. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. AU - MahmoudianDehkordi, S.* AU - Arnold, M. AU - Nho, K.* AU - Ahmad, S.* AU - Jia, W.* AU - Xie, G.* AU - Louie, G.* AU - Kueider-Paisley, A.* AU - Moseley, M.A.* AU - Thompson, K.* AU - St John Williams, L.* AU - Tenenbaum, J.D.* AU - Blach, C.* AU - Baillie, R.A.* AU - Han, X.* AU - Bhattacharyya, S.* AU - Toledo, J.B.* AU - Schafferer, S.* AU - Klein, S.* AU - Koal, T.* AU - Risacher, S.L.* AU - Kling, M.A.* AU - Motsinger-Reif, A.* AU - Rotroff, D.M.* AU - Jack, J.R.* AU - Hankemeier, T.* AU - Bennett, D.A.* AU - de Jager, P.L.* AU - Trojanowski, J.Q.* AU - Shaw, L.M.* AU - Weiner, M.W.* AU - Doraiswamy, P.M.* AU - van Duijn, C.M.* AU - Saykin, A.J.* AU - Kastenmüller, G. AU - Kaddurah-Daouk, R.* C1 - 54552 C2 - 45663 CY - 360 Park Ave South, New York, Ny 10010-1710 Usa SP - 76-92 TI - Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome. JO - Alzheimers Dement. VL - 15 IS - 1 PB - Elsevier Science Inc PY - 2018 SN - 1552-5260 ER - TY - JOUR AB - Purpose of Review Advances in technology have expanded telemedicine opportunities covering medical practice, research, and education. This is of particular importance in movement disorders (MDs), where the combination of disease progression, mobility limitations, and the sparse distribution of MD specialists increase the difficulty to access. In this review, we discuss the prospects, challenges, and strategies for telemedicine in MDs.Recent Findings Telemedicine for MDs has been mainly evaluated in Parkinson's disease (PD) and compared to in-office care is cost-effective with similar clinical care, despite the barriers to engagement. However, particular groups including pediatric patients, rare MDs, and the use of telemedicine in underserved areas need further research.Summary Interdisciplinary telemedicine and tele-education for MDs are feasible, provide similar care, and reduce travel costs and travel time compared to in-person visits. These benefits have been mainly demonstrated for PD but serve as a model for further validation in other movement disorders. AU - Ovsepian, S.V. AU - O'Leary, V.B. AU - Zaborszky, L.* AU - Ntziachristos, V. AU - Dolly, O.J.* C1 - 53078 C2 - 44567 CY - 233 Spring St, New York, Ny 10013 Usa SP - 502-513 TI - Synaptic vesicle cycle and amyloid beta: Biting the hand that feeds. JO - Alzheimers Dement. VL - 14 IS - 4 PB - Springer PY - 2018 SN - 1552-5260 ER - TY - JOUR AB - INTRODUCTION: The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. METHODS: Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. RESULTS: Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. DISCUSSION: Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. AU - Toledo, J.B.* AU - Arnold, M. AU - Kastenmüller, G. AU - Chang, R.* AU - Baillie, R.A.* AU - Han, X.* AU - Thambisetty, M.* AU - Tenenbaum, J.D.* AU - Suhre, K. AU - Thompson, K.* AU - John-Williams, L.S.* AU - MahmoudianDehkordi, S.* AU - Rotroff, D.M.* AU - Jack, J.R.* AU - Motsinger-Reif, A.* AU - Risacher, S.L.* AU - Blach, C.* AU - Lucas, J.E.* AU - Massaro, T.* AU - Louie, G.* AU - Zhu, H.* AU - Dallmann, G.* AU - Klavins, K.* AU - Koal, T.* AU - Kim, S.* AU - Nho, K.* AU - Shen, L.* AU - Casanova, R.* AU - Varma, S.* AU - Legido-Quigley, C.* AU - Moseley, M.A.* AU - Zhu, K.* AU - Henrion, M.Y.* AU - van der Lee, S.J.* AU - Harms, A.C.* AU - Demirkan, A.* AU - Hankemeier, T.* AU - van Duijn, C.M.* AU - Trojanowski, J.Q.* AU - Shaw, L.M.* AU - Saykin, A.J.* AU - Weiner, M.W.* AU - Doraiswamy, P.M.* AU - Kaddurah-Daouk, R.* C1 - 50802 C2 - 42888 CY - New York SP - 965-984 TI - Metabolic network failures in Alzheimer's disease-A biochemical road map. JO - Alzheimers Dement. VL - 13 IS - 9 PB - Elsevier Science Inc PY - 2017 SN - 1552-5260 ER -