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We used data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study [<jats:italic>n<\/jats:italic>\u2009=\u2009690, Age at visit 1 (v<jats:sub>1<\/jats:sub>:2004\u20132009): 30-66y, 42.1% male, 55.4% African American] to evaluate relationships between NfL levels and both visit 1 Hcy (Hcy<jats:sub>v1<\/jats:sub>) and time-dependent Hcy concentrations (Hcy<jats:sub>td<\/jats:sub>). Specifically, we examined the relationship between these measures and visit 1 NfL (NfL<jats:sub>v1<\/jats:sub>) as well as annualized change in NfL (\u03b4NfL) over the study period of\u2009~\u20098y [2004\u20132009 (v<jats:sub>1<\/jats:sub>), 2009\u20132013 (v<jats:sub>2<\/jats:sub>) and\/or 2013\u20132017 (v<jats:sub>3<\/jats:sub>)] using mixed effects linear regression models. Hcy<jats:sub>v1<\/jats:sub> was positively associated with NfL<jats:sub>v1<\/jats:sub>, but not with \u03b4NfL. However, when Hcy<jats:sub>td<\/jats:sub> was considered along with time-dependent covariates on multiple-imputed data, both NfL<jats:sub>v1<\/jats:sub> and \u03b4NfL were associated with Hcy<jats:sub>td<\/jats:sub>, with some significant sex difference in the longitudinal association, whereby this relationship was stronger among males. The Hcy exposure obtained from group-based trajectory models, indicated that individuals belonging to the \"High increasing\" group were consistently associated with both higher NfL<jats:sub>v1<\/jats:sub> and faster increase in NfL (overall, fully adjusted, High <jats:italic>vs<\/jats:italic>. Low: \u03b3<jats:sub>0gbtm<\/jats:sub>\u2009=\u2009\u2009+\u20090.226\u2009\u00b1\u20090.058, P\u2009&lt;\u20090.001; \u03b3<jats:sub>1gbtm<\/jats:sub>\u2009=\u2009\u2009+\u20090.022\u2009\u00b1\u20090.007, P\u2009&lt;\u20090.010). Dynamic Hcy exposures (Hcy<jats:sub>td<\/jats:sub> and Hcy<jats:sub>gbtm<\/jats:sub>) were associated with faster rate of increase in NfL over time, reflecting potentially faster rate of axonal degeneration. Further studies are needed in comparable populations to replicate our findings.<\/jats:p>","DOI":"10.1007\/s11357-025-01567-z","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T07:38:24Z","timestamp":1739950704000},"page":"4663-4678","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma homocysteine level and trajectories\u00a0in\u00a0association with longitudinal increase in plasma neurofilament light among urban adults"],"prefix":"10.1007","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1050-4523","authenticated-orcid":false,"given":"May A.","family":"Beydoun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole Noren","family":"Hooten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael F.","family":"Georgescu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hind A.","family":"Beydoun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie T.","family":"Fanelli-Kuczmarski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele K.","family":"Evans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan B.","family":"Zonderman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"issue":"9","key":"1567_CR1","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1093\/gerona\/60.9.1190","volume":"60","author":"HK Kuo","year":"2005","unstructured":"Kuo HK, Sorond FA, Chen JH, Hashmi A, Milberg WP, Lipsitz LA. 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