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However, the association between bIR and peripheral insulin resistance and their effects on cognition remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Here, we analyzed the expression of key genes (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a084) involved in insulin signaling in brain tissue collected from healthy and AD subjects, as well as regulatory microRNAs (miRNAs) in the brain tissue and tissue\u2010derived small extracellular vesicles (sEV). Subsequently, miRNA expression was analyzed in plasma neuron\u2010derived sEV (NDE) of a second cohort consisting of cognitively normal and adjudicated mixed dementia (aMD) subjects, all with type 2 diabetes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Analysis of miRNAs in brain tissue and their sEV revealed significant and concordant dysregulation. NDE demonstrated similar changes in specific miRNA expression, with significant upregulation exclusively in male aMD subjects, and showed correlation with cognition and plasma \u03b2\u2010amyloid (A\u03b2) 1\u201040 and A\u03b21\u201042.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>NDE may serve as a liquid biopsy to determine sex\u2010specific bIR and cognitive impairment.<\/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>Insulin signaling is disrupted in brain tissue with Alzheimer's disease (AD).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>microRNAs (miRNAs) regulate insulin signaling and insulin resistance.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>miRNAs in neuron\u2010derived small extracellular vesicles (sEV) could serve as biomarkers for brain insulin signaling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Brain insulin signaling biomarkers in neuron\u2010derived sEV (NDE) could predict cognitive impairment.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Sex\u2010specific differences exist in brain insulin resistance biomarkers.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70597","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T10:21:06Z","timestamp":1758104466000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["MicroRNA cargo in neuron\u2010derived vesicles as peripheral biomarkers of brain insulin dysregulation"],"prefix":"10.1002","volume":"21","author":[{"given":"Jacob Alexander","family":"Cleary","sequence":"first","affiliation":[{"name":"Department of Internal Medicine\u2010Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangeeta","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang\u2010Chi","family":"Hsu","sequence":"additional","affiliation":[{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Department of Biostatistics and Data Science Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Craft","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Sticht Center for Healthy Aging and Alzheimer's Prevention Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine\u2010Gerontology and Geriatric Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Sticht Center for Healthy Aging and Alzheimer's Prevention Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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