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This study investigated brain age in adults with early\u2010treated classical PKU compared to healthy controls. Thirty early\u2010treated adults with classical PKU (age 19\u201348\u2009years) and 59 age\u2010, sex\u2010, and education\u2010comparable healthy controls underwent structural magnetic resonance imaging (MRI), cognitive and mood assessment, and blood sampling. Brain age was estimated using machine learning models trained to predict brain age from MRI\u2010derived features across the full brain, cortical lobes, or subcortical regions. The brain age gap (BAG)\u2014the difference between brain age and chronological age\u2014was calculated. In addition, white matter lesion load was rated in patients. While patients with PKU showed differences in BAG for four out of eight brain age estimates, only the BAG in the insula was significantly higher in PKU than controls after correcting for multiple comparisons (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>uncor<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20090.006,\n                    <jats:italic>\u03b7<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.07). The cingulate BAG was positively associated with concurrent and historical Phe levels (\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>s<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20090.41\u20130.69,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>uncor<\/jats:italic>\n                    <\/jats:sub>\n                    &lt;\u20090.05) and with white matter lesion load (\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>s<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20090.40,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>uncor<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u20090.034). Further, subcortical and cingulate BAG were linked to cognitive performance (\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>s<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u2009\u22120.41\u20130.38,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>uncor<\/jats:italic>\n                    <\/jats:sub>\n                    &lt;\u20090.05). These correlations did not survive FDR\u2010correction. In conclusion, the elevated insular BAG in adults with early\u2010treated PKU may reflect atypical brain development due to cumulative effects of early\u2010life or lifelong metabolic disturbances. Longitudinal studies are warranted to elucidate brain aging trajectories and their cognitive implications in PKU.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70158","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T04:14:26Z","timestamp":1771388066000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Brain Age in Adult Patients With Early\u2010Treated Phenylketonuria"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9904-9102","authenticated-orcid":false,"given":"Laura","family":"Winiger","sequence":"first","affiliation":[{"name":"Department of Diabetes Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern  Bern Switzerland"},{"name":"Graduate School for Health Sciences, University of Bern  Bern 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T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Hochuli","sequence":"additional","affiliation":[{"name":"Department of Diabetes Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Vardy","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine Royal Oldham Hospital, Northern Care Alliance NHS Foundation Trust  Oldham UK"},{"name":"Manchester Academic Health Sciences Centre, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Radojewski","sequence":"additional","affiliation":[{"name":"Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine  Bern 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