Immune cells that normally protect the body from damage by attacking foreign or infected cells are found in the brains of patients with Alzheimer's disease and related disorders at much higher levels than in healthy brains. The cells appear to contribute to neurodegeneration, but where they were coming from, and how they were primed to accumulate in the brain, was not known.
Researchers at Washington University School of Medicine in St. Louis have now discovered in mice that these immune cells, known as T cells, are receiving their instructions from lymph nodes outside of the brain. The team also showed they can block these instructions to dramatically mitigate neurodegeneration. The discovery reveals a previously unsuspected pathway that could potentially halt or slow the progression of Alzheimer's disease and other diseases collectively called primary tauopathies, which are characterized by the presence of twisted clumps of tau protein that accumulate in the brain.
The study is published Sept. 3 in Nature Neuroscience.
David M. Holtzman, MD , the Barbara Burton and Reuben M. Morriss III Distinguished Professor in WashU Medicine's Department of Neurology and the study's senior author said that uncovering a driver for Alzheimer's that originates outside the brain is exciting because it points to more-accessible and better-understood targets for treatments.
"One of the issues in developing treatments for neurological diseases is that you need to engineer your treatment so that it gets into the brain and past the blood-brain barrier, but we might not actually need to get the drugs into the central nervous system to mitigate neurodegeneration," Holtzman said. "There are lots of ways to manipulate T cells that have been studied extensively and that are approved treatments for other diseases, but many haven't yet been explored for neurodegenerative diseases."
What directs T cells to the brain in Alzheimer's?
Holtzman's lab has been at the forefront of identifying the role of the immune system in driving neurodegenerative disease. In a previous study , his team demonstrated that eliminating T cells in the brain prevented much of the neurodegeneration that normally occurs in mice modeling damage due to tau protein buildup that occurs in Alzheimer's disease and primary tauopathies.
In this latest work, Holtzman's team — including Hao Hu, PhD, a postdoctoral fellow and the study's first author; co-senior author Jason Ulrich, PhD , a professor of neurology; and their collaborators — set out to identify where the immune cells were coming from and what was directing them to the brain. Certain T cells need other immune partners known as dendritic cells to tell them which molecular targets to attack. There are very few dendritic cells, called classical dendritic cells type 1 (cDC1), in the brain. The ones that are present do not seem to interact with the T cells that appear when tau tangles have developed in the brain.
That pointed to origins outside the brain for both the dendritic and T cells. Eliminating dendritic cells from the lymph nodes as well as other locations in mice that ordinarily develop tau tangles and neurodegeneration also wiped out the elevated levels of T cells, particularly CD8 T cells, in the brain and the attendant brain damage. This was true even though there was no change in the levels of tau tangles in the brain.
In addition to these cellular changes, the mice also retained their cognitive abilities, which suggests that halting the activity of the T cells may slow or reduce the cognitive decline characteristic of Alzheimer's disease.
Can blocking T cells open a way to an Alzheimer's therapy?
Holtzman said that while the specific trigger causing dendritic cells to activate the T cells is not known, it is likely that tau-induced damage to brain cells releases material that finds its way from the brain into the lymph nodes in the neck. There, dendritic cells flag that material as a target for T cells to attack.
The identification of this non-brain immune pathway offers several potential therapeutic targets. Holtzman's team is investigating if impeding dendritic cell function in midlife, to match the onset of tau protein tangles, is as effective as blocking it at birth, as in this study. His team is also pursuing ways to identify what specific signal the T cells are using to home in on the brain, in order to block it.
"Until not that long ago, most people, including myself, did not think that the immune response was even involved in neurodegenerative diseases that are due to protein accumulation in the brain," Holtzman said. "That these dendritic cells are involved in neurodegenerative disease is exciting; we've shown they're important, and that they are a potential target for future therapy."
Hu H, Lin P B-C, Zeng C, Li Y, Bosch ME, Emmerson JT, Sharma P, Ohara RA, Dong W, Wu T, Du S, Wenqing Gao W, Jiang H, Yuan L, Bao X, Li S, Vomund AN, Erdmann-Gilmore P, Gu Y, Hu M, Nulman J, Miller TM, Yokoyama WM, Lichti CF, Milbrandt J, Perrin RJ, Kipnis J, Artyomov MN, Murphy, KM, Ulrich JD, Holtzman DM. Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration. Nature Neuroscience. September 3, 2026 DOI: 10.1038/s41593-026-02427-5 .
This work was supported by a Carol and Gene Ludwig Award for Neurodegeneration Research, National Institute of Health grant AG085374, NS090934, the GHR Foundation, the JPB Foundation, Cure Alzheimer's Fund, Rainwater Charitable Foundation, Carol and Gene Ludwig Family Foundation, the Knight Alzheimer's Disease Research Center Neuropathology Core (NIH P30AG066444, NIH P01 AG03991, and NIH P01AG026276), NIH/NIA R37AG034113 and R01AG078667, Alzheimer's Association Research Fellowship AARF -23-1142708, and NIH grant R01-AI129545. We are grateful to E. Reiman, G. Serrano and T. Beach of the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human primary tauopathy brain tissue. The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research. Meningeal tissues were provided and funded by Washington University Translational Human Neurodegenerative Disease Research (THuNDR) Laboratory for Knight ADRC research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
D.M.H. co-founded, has equity, and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Genentech, Denali, and Switch, and consults for Pfizer, Annexon, Novartis, and Roche. J.K. is a co-founder of Pranas Neuro and Rho Bio. T.507 M.M. is a consultant for Ionis Pharmaceuticals, Biogen, and Arbor Biosciences. T.M.M. has licensing agreements with Ionis Pharmaceuticals and C2N Diagnostics. All other authors declare no competing interests.
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