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An important, understudied factor potentially contributing to mixed results is individual differences in aerobic fitness responses to moderate-intensity continuous training (MICT). This trial will test the effects and mechanisms of 6\u00a0months of aerobic exercise tailored on aerobic fitness response to MICT in community-dwelling older adults with early symptomatic AD. We aim to (I) test the effects of aerobic exercise on aerobic fitness, white matter hyperintensity volume (WMHv), and patient-centered outcomes in older adults with early symptomatic AD; (II) determine the best exercise to improve aerobic fitness and reduce non-responses over 6\u00a0months; and (III) examine the mechanisms of aerobic exercise\u2019s action on cognition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This stage II trial is a Sequential, Multiple Assignment, Randomized Trial (SMART). The hypothesis is that MICT augmented with high-intensity interval training (HIIT) or combined aerobic and resistance exercise (CARE) will improve aerobic fitness, WMHv, and AD\/ADRD plasma biomarkers. This trial will enroll 108 dyads (participants and their study partners). Participants (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009108) are randomized using a 2:1 allocation ratio to 3-month MICT or 6-month stretching control. After the initial 3-month intervention period for participants assigned to MICT, aerobic fitness is measured with peak oxygen consumption (VO\n                      <jats:sub>2peak<\/jats:sub>\n                      ) from a cycle-ergometer exercise testing and the\u00a0shuttle walk test to identify non-response (&lt;\u20095% increase). Non-responders are subsequently re-randomized (1:1) to either HIIT or CARE for 3\u00a0months. Responders continue MICT. All participants are followed for an additional 6\u00a0months post-intervention. Primary outcomes are VO\n                      <jats:sub>2peak<\/jats:sub>\n                      measured at 0, 3, 6, 9, and 12\u00a0months and WMHv at 0, 6, and 12\u00a0months. Secondary outcomes include memory, physical function, behavioral and psychological symptoms of dementia (BPSD), quality of life (QoL), caregiver burden, and AD plasma biomarkers. This trial has 80% power, assuming 18% and 25% attrition at 6 and 12\u00a0months, respectively, to detect changes in aerobic fitness.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Individual differences in VO\n                      <jats:sub>2peak<\/jats:sub>\n                      responses were reported in older adults with AD\/ADRD previously but how this affects response to\u00a0exercise\u00a0interventions is unknown, Precision exercise tailored to VO\n                      <jats:sub>2peak<\/jats:sub>\n                      is critical to advance exercise research in AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT05877196. Registered on May 25, 2023.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13063-025-09040-0","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T10:25:09Z","timestamp":1760523909000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Precision exercise in older adults with early Alzheimer\u2019s disease: The study protocol of the FIT-AD Sequential, Multiple Assignment, Randomized Trial (SMART)"],"prefix":"10.1186","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9399-1987","authenticated-orcid":false,"given":"Fang","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Todd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dereck","family":"Salisbury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Maxfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Pruzin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney P.","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danni","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Baena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Coon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"9040_CR1","unstructured":"Association As. 2025 Alzheimer\u2019s disease facts and figures 2025 [Available from: https:\/\/www.alz.org\/alzheimers-dementia\/facts-figures. 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