{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:24:47Z","timestamp":1788233087205,"version":"build-2803163510"},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015595","name":"GHR Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Amyloid deposition occurs decades before symptoms emerge in Alzheimer's disease (AD). We leveraged blood transcriptomics and positron emission tomography (PET) measures of amyloidosis to identify gene networks in the blood that relate to amyloid burden in the brain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Whole\u2010blood RNA sequencing and amyloid PET were leveraged from 1739 cognitively unimpaired participants in the Anti\u2010Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. Linear regression related gene module expression to amyloid covarying for age, sex, education, and\n                      <jats:italic>apolipoprotein E (APOE) \u03b52 and \u03b54 genotypes<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Of the 18 gene modules, one histone gene cluster module was associated with amyloid (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u00a0=\u00a0\u22120.55, false discovery rate\u2010adjusted\n                      <jats:italic>p<\/jats:italic>\n                      value\u00a0=\u00a00.029). We also observed nominal associations for the predicted proportion of activated natural killer (NK) cells (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u00a0=\u00a0\u22120.454,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.02) and CD4+ activated memory T cells (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u00a0=\u00a0\u22120.169,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.03) with amyloid deposition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our results implicate the histone gene cluster on chromosome 6 and immune cell proportions as blood correlates of brain amyloid deposition in preclinical AD.<\/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>Higher expression of network module with histone gene cluster on chromosome 6 associated with lower amyloid levels.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Four histone genes,\n                            <jats:italic>H1\u20105<\/jats:italic>\n                            ,\n                            <jats:italic>H3C3<\/jats:italic>\n                            ,\n                            <jats:italic>H2BC3<\/jats:italic>\n                            ,\n                            <jats:italic>H2AC14<\/jats:italic>\n                            , and\n                            <jats:italic>RRM2<\/jats:italic>\n                            , emerged as key genes driving this association, where\n                            <jats:italic>H1\u20105<\/jats:italic>\n                            emerged as a hub gene for this module.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Pathways, including nucleosome assembly and DNA damage, were enriched in the histone module.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>A higher fraction of activated NK and activated CD4+ T cells was related to lower amyloid burden.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70982","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T11:08:11Z","timestamp":1766142491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Blood gene expression network expression strongly relates to brain amyloid burden"],"prefix":"10.1002","volume":"21","author":[{"given":"Vaibhav A.","family":"Janve","sequence":"first","affiliation":[{"name":"Vanderbilt Memory &amp; Alzheimer's Center Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Vanderbilt Genetics Institute Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mabel","family":"Seto","sequence":"additional","affiliation":[{"name":"Center for Alzheimer Research and Treatment Brigham and Women's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reisa A.","family":"Sperling","sequence":"additional","affiliation":[{"name":"Center for Alzheimer's Research and Treatment Brigham and Women's Hospital, Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Aisen","sequence":"additional","affiliation":[{"name":"Alzheimer's Therapeutic Research Institute Keck School of Medicine University of Southern California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Rissman","sequence":"additional","affiliation":[{"name":"Alzheimer's Therapeutic Research Institute Keck School of Medicine University of Southern California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Ellen I.","family":"Koran","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory &amp; Alzheimer's Center Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Department of Radiology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Logan","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory &amp; Alzheimer's Center Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Vanderbilt Genetics Institute Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel F.","family":"Buckley","sequence":"additional","affiliation":[{"name":"Center for Alzheimer Research and Treatment Brigham and Women's Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Department of Neurology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Melbourne School of Psychological Sciences University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Hohman","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory &amp; Alzheimer's Center Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Vanderbilt Genetics Institute Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"A4 and LEARN Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70291-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70291-0"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70044-9"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01822-2"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12524"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-10-r148"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-53117-w"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13691"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-022-00975-z"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.0387"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51048"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70142-4"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.114.153494"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2024.134"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/1752-0509-1-54"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm563"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0114-2"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr1028"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000431"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.092"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.12.028"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes14020347"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2024.104052"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2990.1999.00171.x"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/la504089g"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.06.038"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.2-148.v1"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2022.11.022"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.75.103004.142443"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.2460\/ajvr.23.12.0283"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004390050630"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.4592"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106192"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13080719"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10101-7"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0101-9"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25115970"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2024.1398026"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106284"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.911635"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioana.2024.05.005"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2020.1748917"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-143054"},{"key":"e_1_2_10_47_1","first-page":"502","article-title":"Depletion of NK cells improves cognitive function in the Alzheimer's disease mouse model","volume":"205","author":"Zhang Y","year":"1950","journal-title":"J Immunol Baltim Md"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2006.00441.x"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00924-14"}],"container-title":["Alzheimer's &amp; 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