{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T03:14:35Z","timestamp":1788146075463,"version":"build-2803163510"},"reference-count":24,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":30,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;amp;D Transl Res &amp;amp; Clin Interv"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Cognitive reserve (CR) reflects variability in cognitive adaptability that modifies the impact of Alzheimer's disease (AD) pathology on cognition. However, blood\u2010based biomarkers of CR have not been established in prodromal AD. We operationalized CR as memory reserve, defined by the attenuation of the cerebrospinal fluid (CSF) phosphorylated tau threonine 181 (pTau181)\u2013memory association and aimed to identify blood DNA methylation (DNAm) loci involved in memory reserve.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We studied 92 amyloid\u2010positive participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with blood DNAm, CSF pTau181, and memory (PHC_MEM) measured at the same visit. Memory was residualized after adjustment for age, sex,\n                      <jats:italic>APOE<\/jats:italic>\n                      \ud835\udf004 allele count, and estimated immune cell\u2010type proportions. For each CpG, linear models tested DNAm, pTau181, and DNAm\u00d7pTau181 interaction; inflation was corrected using the bacon method. In addition, we also identified differentially methylated regions (DMRs). Moreover, we constructed a methylation reserve score (MRS) from loci identified in this cohort at baseline and tested its associations with longitudinal memory using linear mixed\u2010effects models in 88 participants with follow\u2010up information.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      After removing low\u2010variability CpGs, we identified six CpGs with suggestive DNAm\u00d7pTau181 interaction (\n                      <jats:italic>p<\/jats:italic>\n                      value &lt; 1\u00a0\u00d7\u00a010\n                      <jats:sup>\u22125<\/jats:sup>\n                      , none passed a 5% false discovery rate) and 11 DMRs passing multiple\u2010comparisons correction. The suggestive CpGs and significant DMRs mapped to genes implicating synaptic function, vascular\/blood\u2013brain barrier integrity, and immune regulation, with minimal marginal associations with pTau181 or memory, consistent with a moderation model rather than mediation. In this cohort, higher baseline MRS was associated with attenuation of the pTau181\u2013memory association and with slower subsequent memory decline, independent of age, sex, education\n                      <jats:italic>, APOE<\/jats:italic>\n                      \u03b54, and baseline pTau181.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Blood DNAm that moderates the pTau181\u2013memory association may reflect epigenetic correlates of memory reserve (i.e., differential susceptibility to tau\u2010related memory impairment), rather than reflecting variations in pTau181 levels. These DNAm patterns can be summarized as a MRS that, in this cohort, was associated with longitudinal memory trajectories in MCI. Further validation in independent cohorts is warranted.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70257","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:06:57Z","timestamp":1777619217000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blood DNA methylation signature of cognitive reserve moderates the association between CSF tau pathology and memory in prodromal Alzheimer's disease"],"prefix":"10.1002","volume":"12","author":[{"given":"David","family":"Lukacsovich","sequence":"first","affiliation":[{"name":"Division of Biostatistics Department of Public Health Sciences Miller School of Medicine University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan I.","family":"Young","sequence":"additional","affiliation":[{"name":"Dr. John T Macdonald Foundation Department of Human Genetics Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lissette","family":"Gomez","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian W.","family":"Kunkle","sequence":"additional","affiliation":[{"name":"Dr. John T Macdonald Foundation Department of Human Genetics Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixin","family":"Mao","sequence":"additional","affiliation":[{"name":"Division of Biostatistics Department of Public Health Sciences Miller School of Medicine University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Biostatistics Department of Public Health Sciences Miller School of Medicine University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. Steven","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Biostatistics Department of Public Health Sciences Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"Sylvester Comprehensive Cancer Center Miller School of Medicine University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre M.","family":"O'Shea","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatjana","family":"Rundek","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Miami Miller School of Medicine  Miami Florida USA"},{"name":"Evelyn F. McKnight Brain Institute University of Miami School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eden R.","family":"Martin","sequence":"additional","affiliation":[{"name":"Dr. John T Macdonald Foundation Department of Human Genetics Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8311-4251","authenticated-orcid":false,"given":"Lily","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Biostatistics Department of Public Health Sciences Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"Dr. John T Macdonald Foundation Department of Human Genetics Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"},{"name":"Sylvester Comprehensive Cancer Center Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"Evelyn F. McKnight Brain Institute University of Miami School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer's Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23964"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25123"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12480"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.07.219"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2022.10.015"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012728"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.27186"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.59.10.877"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa209"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2021.04.012"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03565-2"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.851"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101551"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2025.19919"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2022.02.015"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000835"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.01.013"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106373"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-1131-9"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts545"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bby085"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.3934\/Neuroscience.2023029"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.194241"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.10.062"}],"container-title":["Alzheimer's &amp; Dementia: Translational Research &amp; Clinical Interventions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/trc2.70257","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/trc2.70257","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/trc2.70257","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:46:51Z","timestamp":1788144411000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/trc2.70257"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":24,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/trc2.70257"],"URL":"https:\/\/doi.org\/10.1002\/trc2.70257","archive":["Portico"],"relation":{},"ISSN":["2352-8737","2352-8737"],"issn-type":[{"value":"2352-8737","type":"print"},{"value":"2352-8737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]},"assertion":[{"value":"2025-12-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70257"}}