Li-Huei Tsai, Ph.D.

Director, The Picower Institute for Learning and Memory; Picower Professor of Neuroscience, Department of Brain and Cognitive Sciences; Senior Associate Member, Broad Institute, Massachusetts Institute of Technology; Co-Director, Alana Down Syndrome Center

Professor Tsai is a leader in understanding the molecular pathophysiology and systems neuroscience of neurological disorders affecting cognition. Her work has brought new mechanisms for learning, memory and neurodegeneration to light and suggests new paths for combatting age-related memory loss.

Landmark discoveries include pinpointing major genetic risk for Alzheimer’s disease among immune genes, identifying chromatin-modifiers and kinases that regulate brain flexibility and ways to target them to improve cognition in Alzheimer’s disease, discovering that genomic integrity is critical for neuronal protection during both aging and neurodegenerative disease, and showing that bolstering gamma rhythm power and coherence with non-invasive sensory stimulation promotes a neuroprotective response among multiple brain cell types including microglia and the vasculature.

In 2019, Dr. Tsai won the Hans Wigzell Prize in Medicine for her innovative research in trying to understand the etiology and possible treatment of Alzheimer’s disease.  She is a recipient of the Mika Salpeter Lifetime Achievement Award of the Society for Neuroscience, Young Investigator Award, Metropolitan Life Foundation, Outstanding Contributor Award of the Alzheimer Research Forum, the NIH Cantoni Lecture Award and the Glenn Award For Research in Biological Mechanisms of Aging.

She is a Fellow of the American Association for the Advancement of Science, a fellow of the National Academy of Medicine and of the National Academy of Inventors, and a member of the Neurodegeneration Consortium and Taiwan’s Academia Sinica.

Dr. Tsai has authored and co-authored more than 160 peer-reviewed articles published in journals such as Nature, Cell, Neuron, Molecular Psychiatry, The Journal of Neuroscience, Nature Neuroscience, and the Proceedings of the National Academy of Sciences.  Her research has been featured in The New York Times, National Geographic and on National Public Radio

On Twitter: @DrLiHueiTsai

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Funded Research

These projects were made possible from Cure Alzheimer's Fund support.

Selected Publications

These published papers resulted from Cure Alzheimer’s Fund support.

Fan, Q., Gayen, M., Singh, N., Gao, F., He, W., Hu, X., Tsai, L. H., & Yan, R. The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology, Journal of Experimental Medicine, June 17, 2019, Read More

Singh, N., Benoit, M. R., Zhou, J., Das, B., Davila-Velderrain, J., Kellis, M., Tsai, L. H., Hu, X., & Yan, R. BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1, Science Advances, June 17, 2022, Read More

Barker, S. J., Raju, R. M., Milman, N. E. P., Wang, J., Davila-Velderrain, J., Gunter-Rahman, F., Parro, C. C., Bozzelli, P. L., Abdurrob, F., Abdelaal, K., Bennett, D. A., Kellis, M., & Tsai, L. H. MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration, Science Translational Medicine, November 3, 2021, Read More

Marco, A., Meharena, H. S., Dileep, V., Raju, R. M., Davila-Velderrain, J., Zhang, A. L., Adaikkan, C., Young, J. Z., Gao, F., Kellis, M., & Tsai, L. H. Mapping the epigenomic and transcriptomic interplay during memory formation and recall in the hippocampal engram ensemble, Nature Neuroscience, October 5, 2020, Read More

Blanchard, J. W., Bula, M., Davila-Velderrain, J., Akay, L. A., Zhu, L., Frank, A., Victor, M. B., Bonner, J. M., Mathys, H., Lin, Y. T., Ko, T., Bennett, D. A., Cam, H. P., Kellis, M., & Tsai, L. H. Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes, Nature Medicine, June 8, 2020, Read More

Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J. Z., Menon, M., He, L., Abdurrob, F., Jiang, X., Martorell, A. J., Ransohoff, R. M., Hafler, B. P., Bennett, D. A., Kellis, M., & Tsai, L. H. Single-Cell Transcriptomic Analysis of Alzheimer’s Disease, Nature, May 1, 2019, Read More

Sun, N., Victor, M. B., Park, Y. P., Xiong, X., Scannail, A. N., Leary, N., Prosper, S., Viswanathan, S., Luna, X., Boix, C. A., James, B. T., Tanigawa, Y., Galani, K., Mathys, H., Jiang, X., Ng, A. P., Bennett, D. A., Tsai, L. H., & Kellis, M. Human microglial state dynamics in Alzheimer’s disease progression, Cell, September 28, 2023, Read More

Dileep, V., Boix, C. A., Mathys, H., Marco, A., Welch, G. M., Meharena, H. S., Loon, A., Jeloka, R., Peng, Z., Bennett, D. A., Kellis, M., & Tsai, L. H. Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration, Cell, September 28, 2023, Read More

Xiong, X., James, B. T., Boix, C. A., Park, Y. P., Galani, K., Victor, M. B., Sun, N., Hou, L., Ho, L. L., Mantero, J., Scannail, A. N., Dileep, V., Dong, W., Mathys, H., Bennett, D. A., Tsai, L. H., & Kellis, M. Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion, Cell, September 28, 2023, Read More

Mathys, H., Peng, Z., Boix, C. A., … Kellis, M. & Tsai, L. H. Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology, Cell, September 28, 2023, Read More

Ramamurthy, E., Welch, G., Cheng, J., Yuan, Y., Gunsalus, L., Bennett, D. A., Tsai, L. H., & Pfenning, A. R. Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics, Frontiers in Molecular Neuroscience, January 6, 2023, Read More

Udeochu, J. C., Amin, S., … Tsai, L. H., Subhash, S. C., & Gan, L. Tau activation of microglial cGAS–IFN reduces MEF2C-mediated cognitive resilience, Nature Neuroscience, April 24, 2023, Read More

Sun, N., Akay, L. A., Murdock, M. H., Park, Y., Galiana-Melendez, F., Bubnys, A., Galani, K., Mathys, H., Jiang, X., Ng, A. P., Bennett, D. A., Tsai, L. H., & Kellis, M. Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer’s disease., Nature Aging, June 1, 2023, Read More

Garcia, F. J., Sun, N., Lee, H., Godlewski, B., Mathys, H., Galani, K., Zhou, B., Jiang, X., Ng, A. P., Mantero, J., Tsai, L. H., Bennett, D. A., Sahin, M., Kellis, M., & Heiman, M. Single-cell dissection of the human brain vasculature, Nature, February 14, 2022, Read More

Lin, Y. T., Seo, J., Gao, F., Feldman, H. M., Wen, H. L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., Rueda, R., Kritskiy, O., Abdurrob, F., Peng, Z., Milo, B., Yu, C. J., Elmsaouri, S., Dey, D., Ko, T., Yankner, B. A., … Tsai, L. H. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types., Neuron, June 27, 2018, Read More

Murdock, M. H., & Tsai, L. H. Insights into Alzheimer’s disease from single-cell genomic approaches, Nature Neuroscience, January 2, 2023, Read More

Canter, R. G., Penney, J., & Tsai, L. H. The road to restoring neural circuits for the treatment of Alzheiemer’s disease, Nature, November 10, 2016, Read More

Penney, J., Ralvenius, W. T., & Tsai, L. H. Modeling Alzheimer’s Disease With iPSC-derived Brain Cells, Molecular Psychiatry, August 7, 2019, Read More

Penney, J., Ralvenius, W. T., Loon, A., Cerit, O., Dileep, V., Milo, B., Pao, P. C., Woolf, H., & Tsai, L. H. iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss, Glia, November 15, 2023, Read More

Akay, L. A., Effenberger, A. H., & Tsai, L. H. Cell of all trades: oligodendrocyte precursor cells in synaptic, vascular, and immune function, Genes & Development, February 1, 2021, Read More

Dileep, V., & Tsai, L. H. Three-dimensional chromatin organization in brain function and dysfunction, Current Opinion in Neurobiology, June 7, 2021, Read More

Watson, L. A., & Tsai, L. H. In the loop: how chromatin topology links genome structure to function in mechanisms underlying learning and memory, Current Opinion in Neurobiology, December 23, 2017, Read More

Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Scannail, A. N., Bozzelli, P. L., Samaan, G., Murdock, M. H., von Maydell, D., Effenberger, A. H., Cerit, O., Wen, H. L., Liu, L., Welch, G., Bonner, M., & Tsai, L. H. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity, Cell Stem Cell, August 4, 2022, Read More

Meyer, K., Feldman, H. M., Lu, T., Drake, D., Lim, E. T., Ling, K. H., Bishop, N. A., Pan, Y., Seo, J., Lin, Y. T., Su, S. C., Church, G. M., Tsai, L. H., & Yankner, B. A. REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease, Cell Reports, January 29, 2019, Read More

Grossman, N., Bono, D., Dedic, N., Kodandaramaiah, S. B., Rudenko, A., Suk, H. J., Cassara, A. M., Neufeld, E., Kuster, N., Tsai, L. H., Pascual-Leone, A., & Boyden, E. S. Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields, Cell, June 1, 2017, Read More

Blanchard, J. W., Akay, L. A., Davila-Velderrain, J., von Maydell, D., … Kellis, M., Tsai, L. H. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes, Nature, November 16, 2022, Read More

Paolicelli, R. C., Sierra, A., Stevens, B., et al. Microglia states and nomenclature: A field at its crossroads, Neuron, November 2, 2022, Read More

Welch, G. M., Boix, C. A., Schmauch, E., Davila-Velderrain, J., Victor, M. B., Dileep, V., Bozzelli, P. L., Su, Q., Cheng, J. D., Lee, A., Leary, N. S., Pfenning, A. R., Kellis, M., & Tsai, L. H. Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration, Science Advances, September 28, 2022, Read More