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Previous work highlights a relationship between decreased choline intake and an increased risk for cognitive decline and Alzheimer\u2019s disease (AD). The associations between blood circulating choline and the pathological progression in both mild cognitive impairment (MCI) and AD remain unknown. Here, we examined these associations in\u00a0a cohort of patients with MCI with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort\u00a0with either moderate AD (moderate to frequent neuritic plaques, Braak stage\u2009=\u2009IV) or severe AD (frequent neuritic plaques, Braak stage\u2009=\u2009VI), compared to age-matched controls. Metabolomic analysis was performed on serum from the AD cohort. We then assessed the effects of dietary choline deficiency (Ch\u2212) in 3xTg-AD mice and choline supplementation (Ch+) in APP\/PS1 mice, two\u00a0rodent models of AD. The levels of circulating choline were reduced while pro-inflammatory cytokine TNF\u03b1\u00a0was elevated in serum of both MCI sparse and high pathology cases. Reduced choline and elevated TNF\u03b1 correlated with higher neuritic plaque density and Braak stage. In AD patients, we found reductions in choline, its derivative acetylcholine (ACh), and elevated TNF\u03b1. Choline and ACh levels\u00a0were negatively correlated with neuritic plaque\u00a0load, Braak stage, and TNF\u03b1, but positively correlated with MMSE, and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were significantly associated with circuiting choline levels. In 3xTg-AD mice, the Ch\u2212 diet increased amyloid-\u03b2 levels and tau phosphorylation in cortical tissue, and TNF\u03b1\u00a0in both blood and cortical tissue, paralleling the severe human-AD profile. Conversely, the Ch+\u2009diet increased choline and ACh while reducing amyloid-\u03b2\u00a0and TNF\u03b1\u00a0levels in brains of APP\/PS1 mice. Collectively, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of adequate dietary choline intake to offset disease.<\/jats:p>","DOI":"10.1007\/s00401-023-02616-7","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T05:02:16Z","timestamp":1691384536000},"page":"565-583","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Inflammation and the pathological progression of Alzheimer\u2019s disease are associated with low circulating choline levels"],"prefix":"10.1007","volume":"146","author":[{"given":"Jessica M.","family":"Judd","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paniz","family":"Jasbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Winslow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geidy E.","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Beach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Klein-Seetharaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7722-0533","authenticated-orcid":false,"given":"Ramon","family":"Velazquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,7]]},"reference":[{"key":"2616_CR1","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1001\/JAMANEUROL.2019.2244","volume":"76","author":"ML Alosco","year":"2019","unstructured":"Alosco ML, Stein TD, Tripodis Y, Chua AS, Kowall NW, Huber BR et al (2019) Association of white matter rarefaction, arteriolosclerosis, and tau with dementia in chronic traumatic encephalopathy. 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