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We developed and validated MethylCog, a parsimonious DNA methylation (DNAm) marker of general cognitive ability (g).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      MethylCog was developed using elastic net regression on principal components analysis (PCA) \u2010derived g in a population\u2010based cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a02,069; training\/test split) externally validated (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0112). Criterion validity, MCI discrimination, and specificity relative to GrimAge and Alzheimer's disease (AD) biomarkers were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      MethylCog (29 CpGs) predicted g in the test set (\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u00a0=\u00a00.17) and external cohort (\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u00a0=\u00a00.13), explaining \u223c11% of variance beyond age and sex. MethylCog improved MCI discrimination beyond demographics (\u0394AUC\u00a0=\u00a00.03\u20130.07) and outperformed GrimAge but did not add value beyond cognitive screeners. Exploratory analyses showed no significant associations with AD plasma biomarkers or MRI measures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>MethylCog provides initial evidence that parsimonious DNAm scores can index individual differences in cognitive ability, with potential utility where direct assessment is unavailable.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71421","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:20:13Z","timestamp":1777605613000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Development and validation of MethylCog, a blood DNA methylation proxy for cognition"],"prefix":"10.1002","volume":"22","author":[{"given":"Deirdre M.","family":"O'Shea","sequence":"first","affiliation":[{"name":"Comprehensive Center for Brain Health Department of Neurology Miller School of Medicine University of Miami  Boca Raton Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lukacsovich","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":"Devi","family":"Dhanekula","sequence":"additional","affiliation":[{"name":"Comprehensive Center for Brain Health Department of Neurology Miller School of Medicine University of Miami  Boca Raton 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":"Conor","family":"Galvin","sequence":"additional","affiliation":[{"name":"Comprehensive Center for Brain Health Department of Neurology Miller School of Medicine University of Miami  Boca Raton Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"Joshi","sequence":"additional","affiliation":[{"name":"Comprehensive Center for Brain Health Department of Neurology Miller School of Medicine University of Miami  Boca Raton Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilah","family":"Besser","sequence":"additional","affiliation":[{"name":"Comprehensive Center for Brain Health Department of Neurology Miller School of Medicine University of Miami  Boca Raton Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatjana","family":"Rundek","sequence":"additional","affiliation":[{"name":"Department of Neurology and Evelyn F. 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