Claire J. Cadwallader, Anna M. VandeBunte, D. Luke Fischer, Coty Chen, Valentina E. Diaz, Shannon Y. Lee, Brandon Chan, Argentina Lario-Lago, Julio C. Rojas, Eliana Marisa Ramos, Jessica E. Rexach, Jennifer S. Yokoyama, Joel H. Kramer, Emily W. Paolillo, Rowan Saloner, Kaitlin B. Casaletto
{"title":"BDNF Val66Met多态性调节老年人身体活动和神经认知结果之间的关联","authors":"Claire J. Cadwallader, Anna M. VandeBunte, D. Luke Fischer, Coty Chen, Valentina E. Diaz, Shannon Y. Lee, Brandon Chan, Argentina Lario-Lago, Julio C. Rojas, Eliana Marisa Ramos, Jessica E. Rexach, Jennifer S. Yokoyama, Joel H. Kramer, Emily W. Paolillo, Rowan Saloner, Kaitlin B. Casaletto","doi":"10.1002/trc2.70106","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Increased brain-derived neurotrophic factor (BDNF) release through physical activity (PA) is thought to underlie protective effects of PA on brain aging. The <i>BDNF</i> Val66Met single-nucleotide polymorphism (rs6265) reduces activity-dependent BDNF release and has been linked to early Alzheimer's disease (AD) pathology and cognition. We examined whether <i>BDNF</i> 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.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>One hundred eighty older adults (M<sub>age</sub> = 73.1; SD<sub>age</sub> = 9.1; 61% female; 42% <i>BDNF</i> 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-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and <i>BDNF</i> Val66Met genotyping. One hundred twenty-three of the sample completed comprehensive neuropsychological evaluation. Habitual PA levels were operationalized via average daily step count. Composite z-scores were calculated for cognitive domains of memory and executive functioning.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p><i>BDNF</i> genotype moderated the relationship between PA and plasma p-tau181, whereby higher PA was associated with lower plasma p-tau181 concentration in Val/Val participants only. In moderated mediation analyses examining cognitive outcomes, plasma p-tau181 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-way interaction of PA, <i>BDNF</i> genotype, and sex on plasma GFAP concentration, whereby higher PA was associated with lower plasma GFAP only in Val/Val male participants.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>The Val/Val <i>BDNF</i> genotype may facilitate the neuroprotective relationships of PA, including lower AD-relevant biology and better executive function. We further show there may be a sex-specific 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.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Higher physical activity (PA) is associated with lower phosphorylated tau (p-tau181) in brain-derived neurotrophic factor (<i>BDNF</i>) Val66Met Val/Val carriers.</li>\n \n <li>In Val/Val carriers, p-tau181 mediated the association of PA and executive function.</li>\n \n <li>There was a negative association of PA and glial fibrillary acidic protein (GFAP) in Val/Val male, but not female participants.</li>\n \n <li>The neuroprotective benefits of PA may be more pronounced in <i>BDNF</i> Val/Val carriers.</li>\n \n <li>There may be a sex-specific PA pathway for neuroinflammation in Val/Val males.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70106","citationCount":"0","resultStr":"{\"title\":\"BDNF Val66Met polymorphism moderates associations between physical activity and neurocognitive outcomes in older adults\",\"authors\":\"Claire J. Cadwallader, Anna M. VandeBunte, D. Luke Fischer, Coty Chen, Valentina E. Diaz, Shannon Y. Lee, Brandon Chan, Argentina Lario-Lago, Julio C. Rojas, Eliana Marisa Ramos, Jessica E. Rexach, Jennifer S. Yokoyama, Joel H. Kramer, Emily W. Paolillo, Rowan Saloner, Kaitlin B. Casaletto\",\"doi\":\"10.1002/trc2.70106\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>Increased brain-derived neurotrophic factor (BDNF) release through physical activity (PA) is thought to underlie protective effects of PA on brain aging. The <i>BDNF</i> Val66Met single-nucleotide polymorphism (rs6265) reduces activity-dependent BDNF release and has been linked to early Alzheimer's disease (AD) pathology and cognition. We examined whether <i>BDNF</i> 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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>One hundred eighty older adults (M<sub>age</sub> = 73.1; SD<sub>age</sub> = 9.1; 61% female; 42% <i>BDNF</i> 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-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and <i>BDNF</i> Val66Met genotyping. One hundred twenty-three of the sample completed comprehensive neuropsychological evaluation. Habitual PA levels were operationalized via average daily step count. Composite z-scores were calculated for cognitive domains of memory and executive functioning.</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p><i>BDNF</i> genotype moderated the relationship between PA and plasma p-tau181, whereby higher PA was associated with lower plasma p-tau181 concentration in Val/Val participants only. In moderated mediation analyses examining cognitive outcomes, plasma p-tau181 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-way interaction of PA, <i>BDNF</i> genotype, and sex on plasma GFAP concentration, whereby higher PA was associated with lower plasma GFAP only in Val/Val male participants.</p>\\n </section>\\n \\n <section>\\n \\n <h3> DISCUSSION</h3>\\n \\n <p>The Val/Val <i>BDNF</i> genotype may facilitate the neuroprotective relationships of PA, including lower AD-relevant biology and better executive function. We further show there may be a sex-specific 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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li>Higher physical activity (PA) is associated with lower phosphorylated tau (p-tau181) in brain-derived neurotrophic factor (<i>BDNF</i>) Val66Met Val/Val carriers.</li>\\n \\n <li>In Val/Val carriers, p-tau181 mediated the association of PA and executive function.</li>\\n \\n <li>There was a negative association of PA and glial fibrillary acidic protein (GFAP) in Val/Val male, but not female participants.</li>\\n \\n <li>The neuroprotective benefits of PA may be more pronounced in <i>BDNF</i> Val/Val carriers.</li>\\n \\n <li>There may be a sex-specific PA pathway for neuroinflammation in Val/Val males.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":53225,\"journal\":{\"name\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"volume\":\"11 2\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-06-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70106\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/trc2.70106\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/trc2.70106","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
BDNF Val66Met polymorphism moderates associations between physical activity and neurocognitive outcomes in older adults
INTRODUCTION
Increased brain-derived neurotrophic factor (BDNF) release through physical activity (PA) is thought to underlie protective effects of PA on brain aging. The BDNF Val66Met single-nucleotide polymorphism (rs6265) reduces activity-dependent BDNF release and has been linked to early Alzheimer's disease (AD) pathology and cognition. We examined whether BDNF 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.
METHODS
One hundred eighty older adults (Mage = 73.1; SDage = 9.1; 61% female; 42% BDNF 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-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and BDNF Val66Met genotyping. One hundred twenty-three of the sample completed comprehensive neuropsychological evaluation. Habitual PA levels were operationalized via average daily step count. Composite z-scores were calculated for cognitive domains of memory and executive functioning.
RESULTS
BDNF genotype moderated the relationship between PA and plasma p-tau181, whereby higher PA was associated with lower plasma p-tau181 concentration in Val/Val participants only. In moderated mediation analyses examining cognitive outcomes, plasma p-tau181 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-way interaction of PA, BDNF genotype, and sex on plasma GFAP concentration, whereby higher PA was associated with lower plasma GFAP only in Val/Val male participants.
DISCUSSION
The Val/Val BDNF genotype may facilitate the neuroprotective relationships of PA, including lower AD-relevant biology and better executive function. We further show there may be a sex-specific 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.
Highlights
Higher physical activity (PA) is associated with lower phosphorylated tau (p-tau181) in brain-derived neurotrophic factor (BDNF) Val66Met Val/Val carriers.
In Val/Val carriers, p-tau181 mediated the association of PA and executive function.
There was a negative association of PA and glial fibrillary acidic protein (GFAP) in Val/Val male, but not female participants.
The neuroprotective benefits of PA may be more pronounced in BDNF Val/Val carriers.
There may be a sex-specific PA pathway for neuroinflammation in Val/Val males.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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