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Despite worldwide research efforts, a cure for AD has not been identified. Thus, it is critical to identify preventive strategies that can reduce the risk of or delay the onset of AD. Physical activity (PA) has potential in this regard. This randomized clinical trial aims to (a) test the causal relationship between PA and AD-associated cognitive function for persons with a family history of AD (FH+), (b) determine the moderating role of apolipoprotein epsilon 4 (<jats:italic>APOE4<\/jats:italic>) carrier status on cognition, and (c) assess cerebral structure, cerebral function, and putative biomarkers as mediators of the effects of PA on cognition.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We are recruiting cognitively normal, middle aged (40\u201365\u2009years) sedentary adults with FH+. Participants are randomly assigned to a 12-month PA intervention for 3\u2009days\/week or to a control group maintaining their normal lifestyle. Saliva samples are taken at pre-test to determine <jats:italic>APOE<\/jats:italic> genotype. At pre-, mid-, and post-tests, participants complete a series of cognitive tests to assess information-processing speed, verbal and visual episodic memory, constructional praxis, mnemonic discrimination, and higher-order executive functions. At pre- and post-tests, brain imaging and blood biomarkers are assessed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>We hypothesize that 1) the PA group will demonstrate improved cognition compared with controls; 2) PA-derived cognitive changes will be moderated by <jats:italic>APOE4<\/jats:italic> status; and 3) PA-induced changes in neural and blood biomarkers will contribute to cognitive changes and differ as a function of <jats:italic>APOE4<\/jats:italic> status. Our results may provide important insights into the potential of PA to preserve neurocognitive function in people with a heightened risk of AD due to FH+ and as moderated by <jats:italic>APOE4<\/jats:italic> status. By using sophisticated analytic techniques to assess <jats:italic>APOE<\/jats:italic> as a moderator and neurobiological mechanisms as mediators across trajectories of cognitive change in response to PA, we will advance our understanding of the potential of PA in protecting against AD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03876314\"> NCT03876314<\/jats:ext-link>. Registered March 15, 2019.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12883-020-01732-1","type":"journal-article","created":{"date-parts":[[2020,6,6]],"date-time":"2020-06-06T03:47:48Z","timestamp":1591415268000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The effect of physical activity on cognition relative to APOE genotype (PAAD-2): study protocol for a phase II randomized control trial"],"prefix":"10.1186","volume":"20","author":[{"given":"Kyoung Shin","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis B.","family":"Ganesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel T.","family":"Berry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashonda P.","family":"Mobley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B.","family":"Karper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Labban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher N.","family":"Wahlheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomika M.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Wideman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Etnier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,6]]},"reference":[{"issue":"3","key":"1732_CR1","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.jalz.2019.01.010","volume":"15","author":"Association As","year":"2019","unstructured":"Association As. 2019 Alzheimer's disease facts and figures. 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Subsequently, the IRB annually reviews the protocol and reviews modifications as necessary. Participants in this study provide consent prior to the completion of electronic surveys and are provide written informed consent at the first in-person visit at the pre-test. Participants in this study go through a screening test for cognitive normality before the first visit. Therefore, all participants are considered as being capable of ethically and medically consenting for participation on their own behalf. Individuals who do not meet the inclusion criteria for cognitive normality or for depression are encouraged to speak with their personal physician.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no commercial, financial or any other conflict of interest in this research.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"231"}}