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However, alterations in the bone marrow hematopoietic system in patients with Alzheimer\u2019s disease (AD) and their potential impacts on neuroinflammation and cerebral \u03b2-amyloid (A\u03b2) pathology remain unknown. Here, we report that A\u03b2 accumulates within the bone marrow of patients with AD and is particularly concentrated in the central nervous system-surrounding bones. In 5\u2009\u00d7\u2009FAD and APP\/PS1 mice, two classic mouse AD models, A\u03b2 accumulates within the skull bone marrow prior to substantial cerebral A\u03b2 deposits. Flow cytometry and cell tracking analyses demonstrated that these AD mice exhibit enhanced bone marrow hematopoiesis in B lymphoid lineages, specifically an increase in age-associated B cells (ABCs), accompanied by heightened output of these cells into the brain parenchyma. Furthermore, intracranial A\u03b2 injection into IL-6 knockout mice revealed that A\u03b2 promotes B lymphocyte generation, particularly ABCs, via IL-6 signaling. Single-cell sequencing analysis following intracerebroventricular ABCs injection, combined with in vitro microglial culture studies, demonstrated that bone marrow-derived ABCs directly augment microglial reactivity, ultimately exacerbating A\u03b2 neuropathology and cognitive deficits in AD models. Notably, blockade of IL-6R restricts B-cell activity and ABCs in the bone marrow, delays cerebral A\u03b2 pathology and improves cognition. Our findings reveal the potential involvement of bone marrow-derived B cells in the early cerebral amyloid pathology in two mouse AD models and suggest that these B cells may serve as potential therapeutic candidates for patients with AD.<\/jats:p>","DOI":"10.1038\/s41392-025-02419-0","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T23:01:42Z","timestamp":1758150102000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Bone marrow B lymphopoiesis accelerates early cerebral amyloid pathology"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4037-9855","authenticated-orcid":false,"given":"Jing","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanchen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaobo","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7210-8358","authenticated-orcid":false,"given":"Rui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanjin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyong","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6621-0591","authenticated-orcid":false,"given":"Qiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2665-4155","authenticated-orcid":false,"given":"Xiaochun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"2419_CR1","doi-asserted-by":"publisher","first-page":"3336","DOI":"10.1093\/brain\/awq277","volume":"133","author":"CJ Jack","year":"2010","unstructured":"Jack, C. 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