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Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Higher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pT\n                      <jats:sup>308<\/jats:sup>\n                      AKT1 \/total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>AD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251319463","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T08:01:56Z","timestamp":1743753716000},"page":"667-677","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Alzheimer's disease-related cortical proteins modify the association of brain insulin signaling with cognitive decline"],"prefix":"10.1177","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9821-5928","authenticated-orcid":false,"given":"Han","family":"Tong","sequence":"first","affiliation":[{"name":"Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4076-151X","authenticated-orcid":false,"given":"Vladislav A","family":"Petyuk","sequence":"additional","affiliation":[{"name":"Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4737-2974","authenticated-orcid":false,"given":"Michael","family":"Sendtner","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, University Hospital Wuerzburg, Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Sood","sequence":"additional","affiliation":[{"name":"Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana W","family":"Capuano","sequence":"additional","affiliation":[{"name":"Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7477-8884","authenticated-orcid":false,"given":"Zoe","family":"Arvanitakis","sequence":"additional","affiliation":[{"name":"Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,4,4]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.4001"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(05)70284-2"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2011.08.005"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0048-7"},{"key":"e_1_3_5_6_2","first-page":"1688","article-title":"State of the science on brain insulin resistance and cognitive decline due to Alzheimer's disease","volume":"15","author":"Rhea EM","year":"2024","unstructured":"Rhea EM, Leclerc M, Yassine HN, et al. 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