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Diabetes was defined by medication intake or fasting or non-fasting elevated glucose levels. Dementia status was assessed every 2 to 3 years, during up to 12 years of follow-up. Brain parenchymal fraction (BPF) and white matter hyperintensities volume (WMHV) were selected as markers of neurodegeneration and cerebral SVD respectively. We performed a mediation analysis of the effect of baseline BPF and WMHV (mediators) on the association between diabetes and dementia risk using linear and Cox models adjusted for age, sex, education level, hypertension, hypercholesterolemia, BMI, smoking and alcohol drinking status, APOE-\u03b54 status, and study site.\u00a0At baseline, 8.8% of the participants had diabetes. Diabetes (yes vs. no) was associated with higher WMHV (\u03b2\n                    <jats:sub>diab<\/jats:sub>\n                    \u2009=\u20090.193, 95% CI 0.040; 0.346) and lower BPF (\u03b2\n                    <jats:sub>diab\u00a0<\/jats:sub>\n                    =\u00a0\u22120.342, 95% CI \u22120.474; \u22120.210), as well as with an increased risk of dementia over 12 years of follow-up (HR\n                    <jats:sub>diab\u00a0<\/jats:sub>\n                    =\u00a01.65, 95% CI 1.04; 2.60). The association between diabetes status and dementia risk was statistically mediated by higher WMHV (HRdiab=1.05, 95% CI 1.01; 1.11, mediated part\u2009=\u200910.8%) and lower BPF (HR\n                    <jats:sub>diab\u00a0<\/jats:sub>\n                    =\u00a01.12, 95% CI 1.05; 1.20, mediated part\u2009=\u200922.9%).\u00a0This study showed that both neurodegeneration and cerebral SVD statistically explained almost 30% of the association between diabetes and dementia.\n                  <\/jats:p>","DOI":"10.1007\/s10654-023-01080-7","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T07:02:37Z","timestamp":1704697357000},"page":"409-417","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Understanding the relationship between type-2 diabetes, MRI markers of neurodegeneration and small vessel disease, and dementia risk: a mediation analysis"],"prefix":"10.1007","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2812-0103","authenticated-orcid":false,"given":"Leslie","family":"Grasset","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Frison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Helmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gw\u00e9na\u00eblle","family":"Catheline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"Ch\u00eane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Dufouil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,8]]},"reference":[{"key":"1080_CR1","unstructured":"International Diabetes Federation. 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