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Although the effect of apolipoprotein E (\n                      <jats:italic>APOE<\/jats:italic>\n                      ) \u025b4 on the brain is well\u2010studied, less is known about the effect of family history of AD. We examined the main effects of family history and\n                      <jats:italic>APOE<\/jats:italic>\n                      \u025b4 on brain integrity, in addition to assessing possible additive effects of these two risk factors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Diffusion tensor imaging was performed in 136 middle\u2010aged asymptomatic participants stratified on family history and\n                      <jats:italic>APOE<\/jats:italic>\n                      \u025b4. Mean diffusivity and fractional anisotropy (FA) were entered in factorial analyses to test the effect of AD risk on microstructural brain integrity. We performed a post hoc analysis of the three principal diffusivities (\u03bb1, \u03bb2, \u03bb3) to provide potential additional insight on underlying tissue differences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Parental family history of AD was associated with lower FA in regions of the brain known to be affected by AD, including cingulum, corpus callosum, tapetum, uncinate fasciculus, hippocampus, and adjacent white matter. Contrary to previous reports, there was no main effect of\n                      <jats:italic>APOE<\/jats:italic>\n                      \u025b4; however, there was an additive effect of family history and\n                      <jats:italic>APOE<\/jats:italic>\n                      \u025b4 in which family history\u2013positive participants who were also\n                      <jats:italic>APOE<\/jats:italic>\n                      \u025b4 carriers had the lowest FA compared with the other groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The data indicate that unknown risk factors contained in family history are associated with changes in microstructural brain integrity in areas of the brain known to be affected by AD. Importantly, the results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1016\/j.jalz.2009.11.003","type":"journal-article","created":{"date-parts":[[2010,8,15]],"date-time":"2010-08-15T04:49:21Z","timestamp":1281847761000},"page":"394-403","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":110,"title":["White matter is altered with parental family history of Alzheimer's disease"],"prefix":"10.1002","volume":"6","author":[{"given":"Barbara B.","family":"Bendlin","sequence":"first","affiliation":[{"name":"Geriatric Research Educational and Clinical Center, William S. 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