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The relationship between the impact on disease biology and clinically measurable outcomes in cognition, function, and behavior must be considered when defining the meaningful benefit of early AD therapies. In this review, we discuss: (1) the lack of consideration for biomarkers in the current concept of meaningfulness in AD; (2) the lack of gold standards for determining minimal biologically and clinically important differences (MBCIDs) in AD trials; (3) how the treatment benefits of disease\u2010modifying treatments are cumulative and increase over time; and (4) the different concepts of meaningfulness among key stakeholders. This review utilizes the future clinical biological framework of AD and aims to further integrate and expand the parameters of meaningful benefits toward a precision medicine framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Definition of meaningful benefit from Alzheimer's disease (AD) treatment varies across disease stage and stakeholder perspectives.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Observable and meaningful outcomes must consider the clinical\u2010biological nature of AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Statistically significant effects or outcomes do not always equate to clinically meaningfulness.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Assessment tools must reflect stage\u2010specific subtle changes following treatment.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Real\u2010world evidence will support consensus, definition, and interpretation of clinical meaningfulness.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14425","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T04:25:11Z","timestamp":1734582311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Defining benefit: Clinically and biologically meaningful outcomes in the next\u2010generation Alzheimer's disease clinical care pathway"],"prefix":"10.1002","volume":"21","author":[{"given":"Aya","family":"Elhage","sequence":"first","affiliation":[{"name":"Eisai Inc.  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