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Clinical & Translational Neuroscience Section

Madhav Thambisetty, M.D., Ph.D., Unit Head

Although rapid strides have been made in our understanding of the basic biology of Alzheimer's disease (AD), there is concern that this knowledge has not been translated into earlier diagnosis and/or effective treatments for patients. The overarching goal of research in the Clinical and Translational Neuroscience Section (CTNS) is to comprehensively study the metabolic basis of AD pathogenesis in humans. We first identify critical perturbations in both central and systemic metabolism in the early stages of disease progression and pinpoint the principal regulators of key metabolic pathways that may present plausible targets for disease modification.

Second, we use large real-world clinical datasets to test whether pharmacological manipulations of these metabolic pathways alter the risk of AD.

To achieve these goals, we use several approaches including:

  1. Applying mass spectrometry-based metabolomics and proteomics in combination with transcriptomics for understanding biological mechanisms related to AD pathogenesis
  2. Using a systems-level approach integrating data from multi-OMICs methods, neuroimaging and epidemiology to identify plausible drug targets in AD

Curriculum Vitae

Curriculum Vitae for Madhav Thambisetty, M.D., Ph.D. (PDF, 280K)

Details of Recent Studies

  1. Large-scale proteomic studies implicate abnormal brain metabolism in Alzheimer’s disease
  2. Evidence for Brain Glucose Dysregulation in Alzheimer’s Disease
  3. Alpha2-macroglobulin (A2M) is a marker of neuronal injury in Alzheimer’s disease
  4. Midlife adiposity and the age-at-onset of Alzheimer’s disease
  5. Is there a common biology underlying both obesity and obesity-related behaviors?
  6. Insulin resistance (IR) and its relationship to AD pathology and brain function
  7. Proteome-based blood biomarkers of brain amyloid deposition during aging
  8. Plasma clusterin concentration is related to severity, pathology and progression in AD

From Mechanisms to Medicines: Realizing the DREAM of an Alzheimer’s Cure

Our ongoing ‘OMICS’ studies have identified numerous biochemical pathways that are abnormal in AD including glucose breakdown, fatty acid synthesis and phospholipid metabolism. We have identified several FDA-approved drugs prescribed for non-AD indications that may also target these abnormal pathways. We now propose to test whether prior exposure to these drugs results in protection against AD/dementia in large real-world prescription datasets. This project is called the DREAM (Drug Repurposing for Effective Alzheimer’s Medicines) Study and will test exposures to approximately 20 drugs that we have nominated as ‘candidate AD treatments.’ We will perform these analyses in multiple large prescription datasets from the US (Centers for Medicare Services), UK (Clinical Practice Research Datalink), Sweden/Finland (Nordic Prescription Registries) and Taiwan (National Health Insurance Database) which together represent more than 30 million older individuals. This is a unique study that will combine deep molecular phenotyping (i.e. ‘OMICS’ studies in brain/blood) with big-data analyses of patient-derived health record data to identify novel drug repurposing opportunities in AD. We expect that signals indicating a protective effect against AD with one or more drugs will be provide a sound rationale for subsequent confirmation in randomized clinical trials (RCTs).

Portfolio/Research areas

  1. Mechanisms of Alzheimer's disease pathogenesis
  2. Multi-OMICs approaches to identify biologically relevant biomarkers of Alzheimer's disease
  3. Systems-level approaches integrating multi-OMICs, neuroimaging and epidemiology to identify plausible drug targets in AD

Findings and Publications

  1. Chuang Y-F, Varma VR, An Y, Tanaka T, Davatzikos C, Resnick SM Thambisetty M. Interaction between APOE and Butyrylcholinesterase (BCHE) genes on risk of Alzheimer’s disease in a prospective cohort study. Journal of Alzheimer’s Disease 2020 (in press)  https://pubmed.ncbi.nlm.nih.gov/32250307/
  2. Mahajan UV, Varma VR, Griswold ME, Blackshear CT, An Y, Oommen AM, Varma S, Troncoso JC, Pletnikova O, O'Brien R, Hohman TJ, Legido-Quigley C, Thambisetty M. Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study. PLOS Medicine 17(1):e1003012 (2020) PMCID: PMC6980402
  3. Varma VR, Oommen AM, Varma S, Casanova F, An Y, Andrews RM, O’Brien R, Pletnikova O, Troncoso JC, Toledo J, Baillie R, Arnold M, Kastenmueller G, Nho K, Doraiswamy M, Saykin AJ, Kaddurah-Daouk R, Legido-Quigley C, Thambisetty M. Brain and Blood Metabolite Signatures of Pathology and Progression in Alzheimer’s Disease. PLOS Medicine. 15(1): e1002482 (2018) https://pubmed.ncbi.nlm.nih.gov/29370177/
  4. An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, Chia CW, Egan JM, Ferrucci L, Troncoso J, Levey AI, Lah J, Seyfried NT, Legido-Quigley C, O’ Brien R, Thambisetty M. Evidence for Brain Glucose Dysregulation in Alzheimer’s Disease. Alzheimer’s and Dementia. 14(3):318-329 (2018) PMCID: PMC5866736 https://pubmed.ncbi.nlm.nih.gov/29055815/
  5. Roberts JA, Varma VR, Huang C-W, An Y, Oommen AM, Tanaka T, Ferrucci L, Elango P, Takebayashi T, Harada S, Iida M, Thambisetty M. Blood metabolite signature of metabolic syndrome implicates alterations in amino acid metabolism: findings from the Baltimore Longitudinal Study of Aging (BLSA) and the Tsuruoka Metabolomics Cohort Study (TMCS). International Journal of Molecular Sciences 21(4). pii: E1249 (2020) https://pubmed.ncbi.nlm.nih.gov/32070008/

Recent Publications at PubMed

Publications by Madhav Thambisetty, M.D., Ph.D. at PubMed

Awards & Recognition

In a significant recognition of our work, the American Academy of Neurology (AAN) awards the 2016 Norman Geschwind Prize in Behavioral Neurology to Dr. Madhav Thambisetty. The Geschwind prize is given in recognition of outstanding research contributions to the field of behavioral neurology and is named in honor of Dr. Norman Geschwind, the father of modern Behavioral Neurology.

Norman Geschwind Obituary

Norman Geschwind Wikipedia Article

Public outreach and lectures of general interest

Lecture on 'Insulin Resistance, Adiposity and Risk for Alzheimer's Disease' at the 6th International Workshop on HIV and Aging, Washington, DC, October 2015.

Why are study partners important in Alzheimer’s disease clinical trials?
Video produced by the NIA Office of Communication and Public Liaison. Courtesy: Stephanie Dailey and Margaret Vaughn (OCPL; NIA; NIH)

Adiposity and insulin resistance in Alzheimer’s disease: when state meets trait
Neurology Grand Rounds, Johns Hopkins Bayview Medical Center, May 2014

Medicine for the Public Lecture
Since 1977, NIH researchers have educated the public about biomedical research through yearly "Medicine for the Public" programs. This unique forum, hosted by the NIH Clinical Center, engaged NIH scientists to present state-of-the art research in lay language to the public. Attendees had the singular opportunity not only to learn about basic research from those who did it, but also to understand how that research could diagnose, treat, and prevent disease - and ultimately, preserve health. In this way, Medicine for the Public has contributed to the NIH Clear Communication Initiative, which seeks to improve the nation's health literacy.

Media Coverage

  1. Video press release by the NIA on our work in Molecular Psychiatry (Midlife Adiposity predicts earlier onset of Alzheimer’s dementia, neuropathology and presymptomatic cerebral amyloid accumulation).
  2. Links to some press coverage of our results reporting associations between midlife BMI and AD onset in Molecular Psychiatry:

    Excess Weight at Age 50 Linked to Early Alzheimers Onset

    Midlife Weight Alzheimers

    BMI Predicts How Soon Alzheimers Will Develop
  3. Interview on the BBC World Service on our finding that clusterin is a blood biomarker of Alzheimer’s disease
  4. Interview on Voice of America on our work identifying blood biomarkers for brain amyloid deposition
  5. Medscape story on our finding that plasma apoE concentration is related to extent of brain amyloid deposition
  6. Medscape story on our finding that the CR1 risk variant gene is associated with lower brain amyloid deposition in non-demented older individuals
  7. ScienceDaily story on our findings reporting a lack of association between peripheral insulin resistance and Alzheimer’s neuropathology
  8. Discover magazine story highlighting our CR1 results as one of the top 100 scientific discoveries of 2013 (PDF, 629K)
  9. News Story & Video Report on our findings published in Molecular Psychiatry on the obesity gene FTO and its effects on adiposity, brain function, impulsivity and diet during aging

Commentaries

  1. Blood, brain metabolites could be earlier biomarkers of Alzheimer’s disease
    NIA Featured Research highlight on our recent publication in PLoS MEDICINE Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study.

  2. In the Pipeline-Alzheimer's Disease: New Evidence for Brain Glucose Dysregulation in Alzheimer's Disease. Abnormalities Evident Years Before Clinical Symptoms. Commentary in NEUROLOGY TODAY
  3. Nature Reviews Neurology on our finding that alpha2 macroglobulin (A2M) may be a sex-specific marker of neuronal injury in AD (PDF, 557K)
  4. BRAIN PUZZLE Nature Medicine on our finding that the CR1 risk variant gene is associated with lower brain amyloid deposition in non-demented older individuals (PDF, 529K)
  5. CR1 and the “Vanishing Amyloid” Hypothesis of Alzheimer's Disease (link to paper). See also: commentary in Biological Psychiatry (PDF, 860K).