{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:32:22Z","timestamp":1792441942273,"version":"4.5.0"},"reference-count":145,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000735","name":"University of Cambridge","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000735","id-type":"DOI","asserted-by":"crossref"}]},{"name":"St. Catharine\u2019s College, Cambridge"},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"crossref","award":["204623\/Z\/16\/Z"],"award-info":[{"award-number":["204623\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100018956","name":"Cambridge Biomedical Research Centre","doi-asserted-by":"crossref","award":["BRC-1215-20014"],"award-info":[{"award-number":["BRC-1215-20014"]}],"id":[{"id":"10.13039\/501100018956","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100018956","name":"Cambridge Biomedical Research Centre","doi-asserted-by":"crossref","award":["MR\/W020025\/1"],"award-info":[{"award-number":["MR\/W020025\/1"]}],"id":[{"id":"10.13039\/501100018956","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MRC","award":["MR\/M009041\/1"],"award-info":[{"award-number":["MR\/M009041\/1"]}]},{"name":"NIHR Cambridge Biomedical Research Centre"},{"name":"NIH"},{"name":"NHS"},{"DOI":"10.13039\/501100000276","name":"Department of Health and Social Care","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000276","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Higher educational attainment is observationally associated with lower risk of Alzheimer\u2019s disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer\u2019s disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes and Alzheimer\u2019s disease.<\/jats:p>\n                  <jats:p>Summary statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer\u2019s disease (35 274 cases, 59 163 controls) and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer\u2019s disease; (ii) educational attainment and imaging-derived phenotypes; and (iii) imaging-derived phenotypes and Alzheimer\u2019s disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer\u2019s disease risk.<\/jats:p>\n                  <jats:p>Genetically proxied educational attainment was inversely associated with Alzheimer\u2019s disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95% confidence interval 0.60, 0.80). There were positive associations between genetically predicted educational attainment and four cortical metrics (standard deviation units change in imaging phenotype per one standard deviation increase in genetically predicted years of schooling): surface area 0.30 (95% confidence interval 0.20, 0.40); volume 0.29 (95% confidence interval 0.20, 0.37); intrinsic curvature 0.18 (95% confidence interval 0.11, 0.25); local gyrification index 0.21 (95% confidence interval 0.11, 0.31)]; and inverse associations with cortical intracellular volume fraction [\u22120.09 (95% confidence interval \u22120.15, \u22120.03)] and white matter hyperintensities volume [\u22120.14 (95% confidence interval \u22120.23, \u22120.05)]. Genetically proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with educational attainment [standard deviation units change in years of schooling per one standard deviation increase in respective genetically predicted imaging phenotype: 0.13 (95% confidence interval 0.10, 0.16); 0.15 (95% confidence interval 0.11, 0.19) and 0.12 (95% confidence interval 0.04, 0.19)]. We found no evidence of associations between genetically predicted imaging-derived phenotypes and Alzheimer\u2019s disease. The inverse association of genetically predicted educational attainment with Alzheimer\u2019s disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses.<\/jats:p>\n                  <jats:p>Our results provide support for a protective causal effect of educational attainment on Alzheimer\u2019s disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer\u2019s disease. The protective effect of education on Alzheimer\u2019s disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.<\/jats:p>","DOI":"10.1093\/brain\/awac392","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T17:43:05Z","timestamp":1666892585000},"page":"2059-2074","source":"Crossref","is-referenced-by-count":132,"title":["Educational attainment, structural brain reserve and Alzheimer\u2019s disease: a Mendelian randomization analysis"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3949-2386","authenticated-orcid":false,"given":"Aida","family":"Seyedsalehi","sequence":"first","affiliation":[{"name":"Department of Public Health and Primary Care, University of Cambridge , Cambridge CB2 0SR , UK"},{"name":"Department of Psychiatry, Warneford Hospital, University of Oxford , Oxford OX3 7JX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Warrier","sequence":"additional","affiliation":[{"name":"Autism Research Centre, Department of Psychiatry, University of Cambridge , Cambridge CB2 8AH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0714-0685","authenticated-orcid":false,"given":"Richard A I","family":"Bethlehem","sequence":"additional","affiliation":[{"name":"Autism Research Centre, Department of Psychiatry, University of Cambridge , Cambridge CB2 8AH , UK"},{"name":"Brain Mapping Unit, Department of Psychiatry, University of Cambridge , Cambridge CB2 0SZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin I","family":"Perry","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 8AH , UK"},{"name":"CAMEO, Cambridgeshire and Peterborough NHS Foundation Trust , Cambridge CB4 1PX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Burgess","sequence":"additional","affiliation":[{"name":"MRC Biostatistics Unit, University of Cambridge , Cambridge CB2 0SR , UK"},{"name":"Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge , Cambridge CB2 0BB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8296-1742","authenticated-orcid":false,"given":"Graham K","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 8AH , UK"},{"name":"CAMEO, Cambridgeshire and Peterborough NHS Foundation Trust , Cambridge CB4 1PX , UK"},{"name":"Institute for Molecular Bioscience, University of Queensland , Brisbane 4072 , 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