About

Jan Krumsiek, Ph.D., is an Associate Professor of Physiology and Biophysics and an Associate Professor of Computational Genomics in Computational Biomedicine at Weill Cornell Medicine. He develops and applies novel methods for the analysis of metabolomics and multi-omics data, including pathway-based methods, computational simulations, and machine learning techniques. His special focus is on the inference of metabolic networks from data, providing a condition-specific, unbiased in vivo view on metabolism. Dr. Krumsiek's research primarily addresses the etiology and risk prediction in the fields of diabetes and obesity, and he is transitioning to projects in cancer research. His lab elucidates metabolic associations of drug treatment and clinical parameters across different types of cancer. His work involves the development of computational tools and models to better understand metabolic processes and their implications for disease mechanisms and treatment strategies.

Research topics

• Biology
• Internal medicine
• Medicine
• Biochemistry
• Bioinformatics
• Endocrinology
• Cancer research
• Neuroscience
• Genetics
• Immunology
• Cell biology
• Chemistry

Selected publications

• Metabolomics of Right Ventricular Function in Pulmonary Hypertension

  Circulation Research · 2026-04-15 · 1 citations

  article

  BACKGROUND: The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS: We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS: There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS: We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

  PublisherDOI

• Interplay between age, APOE Ɛ4 and the metabolome in plasma and brain in Alzheimer’s disease

  Translational Psychiatry · 2025-10-31 · 1 citations

  articleOpen access

  Age and the ε4 variant of the apolipoprotein E gene (APOE ε4) are two major drivers of Alzheimer's disease (AD). APOE is also the major determinant of longevity. How age and APOE interact in the development of AD is largely unknown. In this study we integrate metabolomics (N = 274,259) and proteomics (N = 54,219) data in plasma from the UK Biobank with the metabolomics (N = 514) and proteomics (N = 618) data in brain from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) to understand the interplay of age, APOE ε4 and metabolome in the development of AD. We find that levels of β-hydroxybutyrate (BHBA) and branch-chained amino acids (BCAAs) are dysregulated in plasma and brains of AD patients. APOE ε4 carriers manifest significantly higher plasma concentration of BHBA that is detectable as early as 37 years of age and remains high throughout the studied age range of 37-73 whereas the plasma concentrations of BCAAs decline in APOE ε44 carriers after the age of 58 years. Proteomic signatures of APOE ε4, BHBA and BCAAs suggest downregulation of lysosome, immune and insulin-like growth factor (IGF1) transport/uptake pathways in plasma, and downregulation of the tricarboxylic acid (TCA) cycle, neurexins/neuroligins and clathrin-mediated endocytosis pathways in brain. Our data identifies two major shifts in metabolism occurring decades apart over the age course in AD in APOE ε4 carriers. These include early ketogenesis that manifests around late 30 s and gluconeogenesis, which manifests around the age of 60 years.

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• WITHDRAWN: Inflammatory profile changes in response to acute endurance exercise from NULISAseq-based detection of analytes in dried blood spot specimens from half marathon participants

  medRxiv · 2025-02-21

  preprintOpen access

  Withdrawal Statement The authors have withdrawn their manuscript because of incomplete IRB approval. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

  PublisherOA PDFDOI

• Metabolomic signatures of hypocaloric dietary interventions associate with breast cancer risk in the Nurses’ Health Study II

  medRxiv · 2025-08-24

  preprintOpen accessSenior authorCorresponding

  Background: An individual's metabolic state plays a critical role in breast cancer (BC) risk, influenced by factors such as obesity and insulin signaling. Hypocaloric diets induce metabolic changes that influence these metabolic factors, thereby potentially influencing BC risk. However, it remains unclear whether metabolic profiles like those induced by such beneficial diets are associated with BC risk. Methods: We compared the impact of a hypocaloric low-carbohydrate ketogenic diet (KD) and a low-fat diet (LFD) on BC risk in two stages. First, we developed metabolomics-based scores representing the metabolic states resulting from these two hypocaloric diets. Plasma metabolomics data of 43 individuals from two controlled dietary interventions were analyzed (N = 31 KD, N = 12 LFD) and a metabolite-based score was generated for both KD and LFD using diet-induced fold-changes. Second, these scores were applied to metabolomics data from a nested case-control study of participants from the Nurses' Health Study II (NHSII, 1,058 BC cases, 1,054 controls, predominantly premenopausal women). Using multivariable-adjusted models, we assessed the association between the metabolomic scores and BC risk. Results: KD and LFD had similar but distinct metabolic signatures. Both metabolomics scores were positively associated with breast cancer risk in NHSII. Women in the highest quartile of the KD metabolomic score had a 37% increased risk of BC compared to women in the lowest quartile (p=0.021). Similarly, women in the highest quartile of the LFD metabolomic score had a 32% increased BC risk compared to women in the lowest quartile (p=0.008). Similar increases in risk were seen when further adjusting for BMI at age 18 and weight change since age 18. Increased levels of cholesterol esters (CE), particularly CE 22:6, and long-chain polyunsaturated triglycerides were associated with higher risk in both diet scores, while increases in short-chain, more saturated triglycerides were associated with lower risk. Conclusion: Metabolomic profiles resembling those induced by hypocaloric ketogenic and low-fat diets were unexpectedly associated with an increased risk of breast cancer in a predominantly premenopausal cohort. These associations were independent of BMI, highlighting the complex relationship between metabolic states and cancer risk, independent of actual dietary interventions.

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• Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer’s disease in humans

  Communications Medicine · 2025-01-08 · 10 citations

  articleOpen access

  Alzheimer’s disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear. In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform. Here we identified substantial changes in response to MMKD intervention, aside from metabolic changes associated with a ketogenic diet, we identified a a global elevation across all plasmanyl and plasmenyl ether lipid species, with many changes linked to clinical and biochemical markers of AD. We further validated our findings by leveraging our prior clinical studies into lipid related changeswith AD (n = 1912), and found that the lipidomic signature with MMKD was inversely associated with the lipidomic signature of prevalent and incident AD. Intervention with a MMKD was able to alter the plasma lipidome in ways that contrast with AD-associated patterns. Given its low risk and cost, MMKD could be a promising approach for prevention or early symptomatic treatment of AD. Previous research has suggested that different diets might alter the risk of a person developing Alzheimer’s disease. We compared the blood of 20 older adults, some with memory impairment, following a change in diet. The two diets we compared were the Modified Mediterranean Ketogenic and American Heart Association Diets. The changes that were seen following consumption of the Mediterranean-ketogenic diet were the opposite to those typically seen in people with Alzheimer’s disease or those likely to develop it. These data suggest adopting this diet could potentially be a promising approach to slow down or prevent the development of Alzheimer’s disease. Aligning these results with previous larger clinical studies looking at lipids, we identified that these changes were opposite to what was typically seen in people with Alzheimer’s disease or those likely to develop it. As this diet was generally safe and inexpensive, this intervention could be a promising approach to mitigate some risk Alzheimer’s disease and help with early symptoms. Neth, Huynh et al. evaluate whether consuming a modified Mediterranean ketogenic diet alters parts of the plasma lipidome associated with development of Alzheimer’s disease (AD). Consuming the ketogenic diet alters the plasma lipidome, with changes inversely linked to Alzheimer’s disease (AD) biomarkers and lipidomic signatures.

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• Individual bioenergetic capacity as a potential source of resilience to Alzheimer’s disease

  Nature Communications · 2025-02-24 · 16 citations

  articleOpen accessSenior author

  Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.

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• Sphingolipid and ceramide associations with tau pathology vary across diverse ethnoracial groups in postmortem brain tissue

  medRxiv · 2025-11-06

  preprintOpen accessSenior authorCorresponding

  Metabolic dysregulation is a hallmark of Alzheimer's disease (AD), with numerous studies characterizing metabolic pathways associated with AD onset and progression. A significant limitation of these studies has been a predominant focus on non-Hispanic white participants. Despite evidence that AD prevalence, progression, and biomarkers differ across ethnoracial groups, it remains unclear whether previously identified metabolic dysregulation in AD brains generalizes across populations. We addressed this gap by analyzing large-scale metabolomics data from 547 postmortem dorsolateral prefrontal cortex brain tissue samples of Hispanic American, Non-Hispanic African American, and White subjects, providing the largest multiethnic AD brain cohort analyzed to date. A metabolome-wide association study examined how relationships between metabolite abundance and AD neuropathology varied by ethnoracial group. Sixty metabolites exhibited significant heterogeneity with tau pathology (Braak stage), with enrichment in tricarboxylic-acid-cycle intermediates, dipeptides, and sphingolipid-ceramide pathway lipids. These findings reveal ethnoracial-specific metabolic signatures of tau pathology and emphasize the need to evaluate emerging therapeutic targets across diverse groups.

  PublisherOA PDFDOI

• AutoFocus: a hierarchical framework to explore multi-omic disease associations spanning multiple scales of biomolecular interaction

  Communications Biology · 2024-09-05 · 1 citations

  articleOpen accessSenior author

  Recent advances in high-throughput measurement technologies have enabled the analysis of molecular perturbations associated with disease phenotypes at the multi-omic level. Such perturbations can range in scale from fluctuations of individual molecules to entire biological pathways. Data-driven clustering algorithms have long been used to group interactions into interpretable functional modules; however, these modules are typically constrained to a fixed size or statistical cutoff. Furthermore, modules are often analyzed independently of their broader biological context. Consequently, such clustering approaches limit the ability to explore functional module associations with disease phenotypes across multiple scales. Here, we introduce AutoFocus, a data-driven method that hierarchically organizes biomolecules and tests for phenotype enrichment at every level within the hierarchy. As a result, the method allows disease-associated modules to emerge at any scale. We evaluated this approach using two datasets: First, we explored associations of biomolecules from the multi-omic QMDiab dataset (n = 388) with the well-characterized type 2 diabetes phenotype. Secondly, we utilized the ROS/MAP Alzheimer's disease dataset (n = 500), consisting of high-throughput measurements of brain tissue to explore modules associated with multiple Alzheimer's Disease-related phenotypes. Our method identifies modules that are multi-omic, span multiple pathways, and vary in size. We provide an interactive tool to explore this hierarchy at different levels and probe enriched modules, empowering users to examine the full hierarchy, delve into biomolecular drivers of disease phenotype within a module, and incorporate functional annotations.

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• Bidirectional modulation of TCA cycle metabolites and anaplerosis by metformin and its combination with SGLT2i

  Research Square · 2024-02-09

  preprintOpen access

  Abstract Background Metformin and sodium-glucose-cotransporter-2 inhibitor (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes, yet their nuanced impacts on metabolic processes, particularly in the citric acid (TCA) cycle and its anaplerotic pathways, are not fully delineated. This study aims to investigate the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions. Methods Our study employed a three-pronged approach: first, comparing metformin-treated diabetic mice (MET) with vehicle-treated controls (VG) and non-diabetic wild types (WT) to identify metformin-specific metabolic changes; second, assessing these changes in human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients; third, contrasting MET with those on combination therapy (SGLT2i + MET). Metabolic profiling was conducted on 716 metabolites from plasma, liver, and kidney tissues post-treatment. Linear regression analysis and Bonferroni correction were used for rigorous statistical evaluation across all comparisons, complemented by pathway analyses to elucidate the pathophysiological implications of the metabolites involved. Results Metformin monotherapy was significantly associated with upregulation of TCA cycle intermediates, such as malate, fumarate, and α-ketoglutarate (α-KG), in plasma, along with anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Conversely, downregulated hepatic taurine was observed. However, the addition of SGLT2i reversed these metabolic effects, indicating a complex interplay between these antidiabetic drugs in regulating the central energy metabolism. Human T2D subjects on metformin therapy exhibited significant systemic alterations in metabolites, including increased malate but decreased citrulline. The drugs' bidirectional modulation of TCA cycle intermediates appeared to influence four key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. Conclusion This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle and beyond, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like non-alcoholic fatty liver disease (NAFLD). These observations highlight the potential for repurposing these drugs for broader therapeutic applications and underscore the importance of personalized treatment strategies.

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• Bidirectional modulation of TCA cycle metabolites and anaplerosis by metformin and its combination with SGLT2i

  Cardiovascular Diabetology · 2024-06-12 · 6 citations

  articleOpen access

  BACKGROUND: Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. METHODS: Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. RESULTS: Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. CONCLUSION: This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

  PublisherOA PDFDOI

Recent grants

• ADMINISTRATIVE SUPPLEMENT - TargetAD: A systems multi-omics approach to drug repositioning in Alzheimer's disease

  NIH · $625k · 2021–2026

Frequent coauthors

• Gabi Kastenmüller

  Helmholtz Zentrum München

  343 shared

• Karsten Suhre

  Weill Cornell Medicine

  245 shared

• Jerzy Adamski

  University of Ljubljana

  198 shared

• Fabian J. Theis

  Technical University of Munich

  187 shared

• Elisa Benedetti

  Cornell University

  158 shared

• Richa Batra

  Cornell University

  154 shared

• Mustafa Büyüközkan

  Lander Institute

  154 shared

• Matthias Arnold

  Emory University

  150 shared