{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T01:40:11Z","timestamp":1790386811770,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":79,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005331","name":"American Brain Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005331","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005339","name":"American Academy of Neurology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>\n                      Increased brain\u2010derived neurotrophic factor (BDNF) release through physical activity (PA) is thought to underlie protective effects of PA on brain aging. The\n                      <jats:italic>BDNF<\/jats:italic>\n                      Val66Met single\u2010nucleotide polymorphism (rs6265) reduces activity\u2010dependent BDNF release and has been linked to early Alzheimer's disease (AD) pathology and cognition. We examined whether\n                      <jats:italic>BDNF<\/jats:italic>\n                      genotype influences the association of PA with plasma markers of AD, axonal degeneration, and neuroinflammation, along with consequences for cognition, in older adults without dementia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      One hundred eighty older adults (M\n                      <jats:sub>age<\/jats:sub>\n                      = 73.1; SD\n                      <jats:sub>age<\/jats:sub>\n                      = 9.1; 61% female; 42%\n                      <jats:italic>BDNF<\/jats:italic>\n                      Met allele carriers) from the University of California San Francisco (UCSF) Memory and Aging Center completed 30 days of actigraphy monitoring, plasma assays of phosphorylated tau (p\u2010tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and\n                      <jats:italic>BDNF<\/jats:italic>\n                      Val66Met genotyping. One hundred twenty\u2010three of the sample completed comprehensive neuropsychological evaluation. Habitual PA levels were operationalized via average daily step count. Composite z\u2010scores were calculated for cognitive domains of memory and executive functioning.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      <jats:italic>BDNF<\/jats:italic>\n                      genotype moderated the relationship between PA and plasma p\u2010tau181, whereby higher PA was associated with lower plasma p\u2010tau181 concentration in Val\/Val participants only. In moderated mediation analyses examining cognitive outcomes, plasma p\u2010tau181 selectively mediated the relationship between PA and executive function in Val\/Val participants. In analyses including sex as a biological factor, there was a three\u2010way interaction of PA,\n                      <jats:italic>BDNF<\/jats:italic>\n                      genotype, and sex on plasma GFAP concentration, whereby higher PA was associated with lower plasma GFAP only in Val\/Val male participants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      The Val\/Val\n                      <jats:italic>BDNF<\/jats:italic>\n                      genotype may facilitate the neuroprotective relationships of PA, including lower AD\u2010relevant biology and better executive function. We further show there may be a sex\u2010specific negative relationship of PA with neuroinflammation in Val\/Val males. These results further elucidate sources of individual variation observed in relationships between PA and brain health and will contribute to guiding personalized neurotrophic treatments for older adults.\n                    <\/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>\n                            Higher physical activity (PA) is associated with lower phosphorylated tau (p\u2010tau181) in brain\u2010derived neurotrophic factor (\n                            <jats:italic>BDNF<\/jats:italic>\n                            ) Val66Met\u00a0Val\/Val carriers.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In Val\/Val carriers, p\u2010tau181 mediated the association of PA and executive function.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>There was a negative association of PA and glial fibrillary acidic protein (GFAP) in Val\/Val male, but not female participants.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The neuroprotective benefits of PA may be more pronounced in\n                            <jats:italic>BDNF<\/jats:italic>\n                            Val\/Val carriers.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>There may be a sex\u2010specific PA pathway for neuroinflammation in Val\/Val males.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70106","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T01:05:04Z","timestamp":1750381504000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<i>BDNF<\/i>\n                    Val66Met polymorphism moderates associations between physical activity and neurocognitive outcomes in older adults"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3449-3803","authenticated-orcid":false,"given":"Claire J.","family":"Cadwallader","sequence":"first","affiliation":[{"name":"Department of Neurology Memory and Aging Center Weill Institute for Neurosciences University of California  San Francisco USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"VandeBunte","sequence":"additional","affiliation":[{"name":"Department of Neurology Memory and Aging Center Weill Institute for Neurosciences University of California  San Francisco USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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