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Grey matter (GM) volume differences were analyzed using voxel\u2010based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Significantly more mammillary body atrophy in <jats:italic>+<\/jats:italic>EOAD compared to \u2013EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in <jats:italic>+<\/jats:italic>LOAD compared to \u2013LOAD. Medial temporal GM volume loss was also found in <jats:italic>+<\/jats:italic>EOAD compared to \u2013LOAD. With an exception for <jats:italic>+<\/jats:italic>EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in <jats:italic>\u2013<\/jats:italic>LOAD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results show that the <jats:italic>APOE<\/jats:italic> genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD <jats:italic>APOE4<\/jats:italic> genotype is mostly associated with increased medial temporal and parietal atrophy compared to <jats:italic>\u2013<\/jats:italic>LOAD, for EOAD <jats:italic>APOE4<\/jats:italic> might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that <jats:italic>APOE<\/jats:italic> genotype needs to be taken into account when classifying patients by age at onset.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.15657","type":"journal-article","created":{"date-parts":[[2022,12,4]],"date-time":"2022-12-04T11:54:20Z","timestamp":1670154860000},"page":"597-605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The <scp><i>APOE4<\/i><\/scp> effect: structural brain differences in Alzheimer's disease according to the age at symptom onset"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2739-6028","authenticated-orcid":false,"given":"Gonzalo","family":"Forno","sequence":"first","affiliation":[{"name":"Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Cl\u00ednic of Barcelona Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona  Barcelona Spain"},{"name":"School of Psychology Universidad de los Andes  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9692-1570","authenticated-orcid":false,"given":"Jose","family":"Contador","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Cl\u00ednic of Barcelona Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3006-9792","authenticated-orcid":false,"given":"Agn\u00e8s","family":"P\u00e9rez\u2010Millan","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Cl\u00ednic of Barcelona Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona  Barcelona Spain"},{"name":"Institute of Neurosciences. 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