{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T22:10:09Z","timestamp":1793916609140,"version":"4.8.0"},"reference-count":98,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Physical activity (PA) is often proposed as a modifiable strategy to reduce cognitive decline and dementia risk, particularly among individuals at elevated genetic risk for Alzheimer\u2019s disease (AD). However, it remains unclear whether the existing literature tests PA at the disease stage and in the populations most likely to show benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      This umbrella review evaluated whether associations between PA and cognitive, fluid biomarker, neuroimaging, and vascular\/metabolic outcomes differ by apolipoprotein E \u03b54 (\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54) genotype across stages of cognitive aging, with particular attention to how study design and baseline cognitive status shape interpretation of the evidence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Systematic reviews and meta-analyses were screened for primary studies examining PA in adults classified by baseline cognitive status as cognitively unimpaired, mild cognitive impairment (MCI), or dementia. Primary studies reporting\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54-stratified outcomes were extracted and qualitatively synthesized by outcome domain, cognitive stage, and study design.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 2,100 records identified, seven systematic reviews met inclusion criteria, yielding 68 unique primary studies. Favorable associations between PA and cognitive, biomarker, neuroimaging, and vascular\/metabolic outcomes were most often reported in observational studies of younger or cognitively unimpaired adults. Several studies suggested stronger associations among\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 carriers, including midlife cognitive associations, neuroimaging markers, and vascular\/metabolic outcomes such as lipid profiles. In contrast, randomized controlled trials were few, generally enrolled older adults with MCI or dementia, included small\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 subgroups, and reported largely null or mixed genotype-specific effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The current evidence does not establish a definitive\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54-specific preventive effect of PA. Future studies may be most informative if they target earlier-stage, low-active, or metabolically at-risk\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 carriers using objective PA measures and proximal vascular, metabolic, imaging, or blood-based biomarker outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1798639","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:38:25Z","timestamp":1784785105000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["APOE \u03b54, physical activity, and the brain: a review of systematic reviews"],"prefix":"10.3389","volume":"18","author":[{"given":"Nada","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelle","family":"Chakbazof","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Ghasem Pour","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Contreras","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimena","family":"Estrada","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gene E.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Department of Psychiatry, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Neuroscience Graduate Interdisciplinary Program, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Physiological Sciences Graduate Interdisciplinary Program, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Evelyn F. McKnight Brain Institute, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Arizona Alzheimer\u2019s Consortium","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Raichlen","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussein N.","family":"Yassine","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Southern California","place":["Los Angeles, CA, United States"]},{"name":"Department of Biological Sciences, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.3390\/ijms27021004","article-title":"Apolipoprotein E4 in Alzheimer's disease: role in pathology, lipid metabolism, and drug treatment","volume":"27","author":"Al-Ghraiybah","year":"2026","journal-title":"Int. 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