Clinical & Translational Neuroscience Section

Although rapid strides have been made in understanding the basic biology of Alzheimer's disease (AD), 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 biologic 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/signaling 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.
  3. Validating plausible drug candidates through analyses of large real world clinical datasets in initiatives such as the Drug Repurposing for Effective Alzheimer’s Medicines (DREAM)
  4. Testing candidate AD drugs through experimental validation in cell culture based phenotypic screens as well as transgenic models

Curriculum Vitae

(PDF, 325K)

Details of Recent Studies

  1. Is Alzheimer's Risk Lower With TNF Inhibitors? For arthritis patients with cardiovascular disease, the answer may be yes
  2. NIA Study Identifies FDA Approved Drugs May Also be Helpful for Dementia
  3. Young ApoE4 Carriers Have Reversed AD Proteomic Signature
  4. Abnormal cholesterol metabolism linked to dementia risk
  5. Evidence for brain glucose dysregulation in Alzheimer’s disease
  6. Polyamines–What role in neurodegeneration?
  7. Large-scale proteomic studies implicate abnormal brain metabolism in Alzheimer’s disease

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

OOur 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) and UK (Clinical Practice Research Datalink), which together represent more than 20 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).

Please click here for a Video Abstract of the DREAM Study on NIA’s Youtube page:

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

Key Recent Publications

  1. Varma VR, Desai RJ, Navakkode S, Wong L-W, Anerillas C, Loeffler T, Schilcher I, Mahesri M, Chin K, Horton DB, Kim SC, Gerhard T, Segal JB, Schneeweiss S, Gorospe M, Sajikumar S and Thambisetty M. Hydroxychloroquine lowers Alzheimer’s disease and related dementias risk and rescues molecular phenotypes related to Alzheimer’s disease. Molecular Psychiatry. (2022) 28(3):1312-1326 PMID: 36577843 PMCID: PMC10005941
  2. Desai RJ, Mahesri M, Lee SB, Varma VR, Loeffler T, Schilcher I, Gerhard T, Segal JB, Ritchey ME, Horton DB, Kim SC, Schneeweiss S and Thambisetty M. No association between initiation of phosphodiesterase-5 inhibitors and risk of incident Alzheimer’s disease and related dementia: results from the Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) study. Brain Communications. 2022 4(5): fcac247 PMID: 36330433 PMCID: PMC9598543
  3. Desai RJ, Varma V, Gerhard T, Segal J, Mahesri M, Chin K, Horton DM, Kim SC, Schneeweiss S, Thambisetty M. Comparative risk of Alzheimer’s disease and related dementia among Medicare beneficiaries with rheumatoid arthritis treated with targeted disease modifying antirheumatic agents JAMA Network Open (2022) PMCID: PMC8994126
  4. Roberts JA, Varma VR, An Y, Varma S, Candia J, Fantoni G, Tiwari V, Anerillas C, Williamson A, Saito A, Loeffler T, Schilcher I, Moaddel R, Khadeer M, Lovett J, Tanaka T, Pletnikova O, Troncoso JC, Bennett DA, Albert MS, Yu K, Niu M, Haroutunian V, Zhang B, Peng J, Croteau DL, Resnick SM, Gorospe M, Bohr VA, Ferrucci L, Thambisetty M. A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets. Sci Adv. 2021 Nov 12;7(46):eabi8178. doi: 10.1126/sciadv.abi8178. Epub 2021 Nov 10.PMID: 34757788
  5. Varma VR, Büşra Lüleci H, Oommen AM, Varma S, Blackshear CT, Griswold ME, An Y, Roberts JA, O'Brien R, Pletnikova O, Troncoso JC, Bennett DA, Çakır T, Legido-Quigley C, Thambisetty M. Abnormal brain cholesterol homeostasis in Alzheimer's disease-a targeted metabolomic and transcriptomic study. NPJ Aging Mech Dis. 2021 Jun 1;7(1):11. doi: 10.1038/s41514-021-00064-9.PMID: 34075056
  6. Varma VR, Wang Y, An Y, Varma S, Bilgel M, Doshi J, Legido-Quigley C, Delgado JC, Oommen AM, Roberts JA, Wong DF, Davatzikos C, Resnick SM, Troncoso JC, Pletnikova O, O'Brien R, Hak E, Baak BN, Pfeiffer R, Baloni P, Mohmoudiandehkordi S, Nho K, Kaddurah-Daouk R, Bennett DA, Gadalla SM, Thambisetty M. Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study. PLoS Med. 2021 May 27;18(5):e1003615. doi: 10.1371/journal.pmed.1003615. eCollection 2021 May.PMID: 34043628
  7. Desai RJ, Varma VR, Gerhard T, Segal J, Mahesri M, Chin K, Nonnenmacher E, Gabbeta A, Mammen AM, Varma S, Horton DB, Kim SC, Schneeweiss S, Thambisetty M. Targeting abnormal metabolism in Alzheimer's disease: The Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study. Alzheimers Dement (N Y). 2020 Nov 26;6(1):e12095. doi: 10.1002/trc2.12095. eCollection 2020.PMID: 33304987
  8. 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 Med. 2020 Jan 24;17(1):e1003012. doi: 10.1371/journal.pmed.1003012. eCollection 2020 Jan.PMID: 31978055

A full list of Publications is available here:

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

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

NIH Director’s seminar series https://videocast.nih.gov/watch=38520

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. Alzheimer’s clinical trials have a recruitment problem. Telehealth platform Ro thinks it can help
  2. Some arthritis drugs may reduce Alzheimer’s and related dementias risk in those with heart disease
  3. Repurposed cancer treatments could be potential Alzheimer’s drugs
  4. 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).
  5. Links to some press coverage of our results reporting associations between midlife BMI and AD onset in Molecular Psychiatry:
  6. Interview on the BBC World Service on our finding that clusterin is a blood biomarker of Alzheimer’s disease
  7. Medscape story on our finding that plasma apoE concentration is related to extent of brain amyloid deposition
  8. Medscape story on our finding that the CR1 risk variant gene is associated with lower brain amyloid deposition in non-demented older individuals
  9. ScienceDaily story on our findings reporting a lack of association between peripheral insulin resistance and Alzheimer’s neuropathology
  10. (PDF, 629K)

Commentaries

  1. Young ApoE4 Carriers Have Reversed AD Proteomic Signature Alzforum write up on our work describing early proteomic changes in the brains of young APOE4 carriers. .
  2. No association of Viagra and Cialis with reduced Alzheimer's disease An important negative result from the DREAM study reporting lack of evidence for the use of PDE5 inhibitors in Alzheimer’s disease.
  3. Innovative study to determine whether medicines currently FDA-approved to treat conditions other than dementia can help prevent or treat Alzheimer disease. Report in Neurology Live on the DREAM study
  4. Is Alzheimer's Risk Lower With TNF Inhibitors? MEDPAGE TODAY report on findings from DREAM study on associations between TNF inhibitors and risk of Alzheimer’s disease
  5. Blood, brain metabolites could be earlier biomarkers of Alzheimer’s disease NIA Featured Research highlight on our recent publication in PLoS MEDICINE