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Obesity has frequently been shown to affect brain physiology at multiple levels, and to increase the risk for the development of neuropsychiatric disorders such as major depression and dementia. Previous large-scale neuroimaging research has consistently shown overlapping brain structural alterations in obesity and neuropsychiatric disorders, with the most pronounced alterations being lower cortical thickness in the frontal and temporal cortex. Yet, the direction of association, and the potential causal effect of obesity on brain structural decline, remains unclear. Moreover, it is imperative to determine which of the multifaceted biological systems impacted by obesity, encompassing metabolic, cardiovascular, and inflammatory aspects, may be implicated in the link between obesity and brain structural decline. In this study, we employed univariate and multivariate Mendelian randomization (MR) as an instrumental variable (IV) approach to clarify the causal direction of the relationship between body mass index (BMI) and brain structure and to disentangle the metabolic, cardiovascular, and inflammatory factors that might underlie this relationship. We found evidence for a potential causal influence of elevated BMI on lower cortical thickness, with the most prominent effects in the precentral and fusiform gyrus. We furthermore found concurrent nominal associations of visceral adipose tissue (VAT) and the inflammatory serum marker CRP with lower cortical thickness which largely overlapped with regions associated with higher BMI. In contrast, very few associations with cortical thickness emerged for blood pressure or metabolic serum markers. Our findings thus corroborate the notion of a causal effect of BMI on lower cortical thickness. Future research should aim to delineate if and how the BMI related effect on brain structural decline conveys an increased risk for the development of neuropsychiatric disorders.<\/jats:p>","DOI":"10.1038\/s41380-026-03501-x","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:43:40Z","timestamp":1773078220000},"page":"4006-4013","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deciphering the causal influence of BMI and related metabolic, inflammatory, and cardiovascular factors on brain structure: a Mendelian Randomization Study"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4992-2458","authenticated-orcid":false,"given":"Jodie N.","family":"Painter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3505-1575","authenticated-orcid":false,"given":"Alexander","family":"Refisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8040-4926","authenticated-orcid":false,"given":"Moritz","family":"Rau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7857-4483","authenticated-orcid":false,"given":"Martin","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7817-7437","authenticated-orcid":false,"given":"Scott","family":"Mackey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Laurent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8539-0228","authenticated-orcid":false,"given":"Katrina L.","family":"Grasby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0281-8458","authenticated-orcid":false,"given":"Tomas","family":"Hajek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-380X","authenticated-orcid":false,"given":"Sarah E.","family":"Medland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-3298","authenticated-orcid":false,"given":"Nils","family":"Opel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"3501_CR1","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1002\/oby.23116","volume":"29","author":"C Bouchard","year":"2021","unstructured":"Bouchard C. 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