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This study addresses this gap by analyzing relative brain volumetric patterns to capture how Alzheimer's disease (AD) and genetics influence brain structure along the disease continuum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>This study analyzed data from participants across the AD continuum from the Alzheimer's and Families (ALFA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. Compositional data analysis (CoDA) was exploited to examine relative brain volumetric variations that (1) were linked to different AD stages compared to cognitively unimpaired amyloid\u2010\u03b2\u2013negative (CU A\u2212) individuals and (2) varied by AD genetic risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Disease stage\u2013specific compositional brain scores were identified, differentiating CU A\u2212 individuals from those in more advanced stages. Genetic risk\u2013stratified models revealed a broader genetic landscape affecting brain morphology in AD, beyond the well\u2010known apolipoprotein E \u03b54 allele.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>CoDA emerges as an alternative multivariate framework to deepen understanding of AD\u2010related structural changes and support targeted interventions for those at higher genetic risk.<\/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>Compositional data analysis (CoDA) revealed the relative variation of brain region volumes, captured in compositional brain scores, capable of discerning between cognitively unimpaired amyloid\u2010\u03b2\u2013negative individuals and subjects within other disease\u2010stage groups along the Alzheimer's disease (AD) continuum.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>CoDA also uncovered the genetic vulnerability of specific brain regions at each stage of the disease along the continuum.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>CoDA is capable of integrating magnetic resonance imaging data from two different cohorts without stringent requirements for harmonization. This translates as an advantage, compared to traditional methods, and strengthens the reliability of cross\u2010study comparisons by standardizing the data despite different labeling agreements, facilitating collaborative and large\u2010scale research.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The algorithm is sensitive to AD\u2010specific effects, as the main compositional brain scores display little overlap with the age\u2010specific compositional brain score.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>CoDA provides a more accurate analysis of brain imaging data addressing its compositional nature, which can influence the development of targeted approaches, opening new avenues for enhancing brain health.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14490","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T05:59:42Z","timestamp":1737957582000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Compositional brain scores capture Alzheimer's disease\u2013specific structural brain patterns along the disease continuum"],"prefix":"10.1002","volume":"21","author":[{"given":"Patricia","family":"Genius","sequence":"first","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center (BBRC) Pasqual Maragall Foundation  Barcelona Spain"},{"name":"Hospital del Mar Research Institute, Barcelona, Spain.  Barcelona Spain"},{"name":"Centre for Genomic Regulation (CRG) Barcelona Institute of Science and Technology (BIST)  Barcelona Spain"},{"name":"Doctoral School PhD programme in Bioinformatics University of Vic\u2013Central University of Catalonia (UVic\u2010UCC)  Vic Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Luz","family":"Calle","sequence":"additional","affiliation":[{"name":"Biosciences Department Faculty of Sciences Technology and Engineering University of Vic\u2013Central University of Catalonia  Vic Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Rodr\u00edguez\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center (BBRC) Pasqual Maragall Foundation  Barcelona Spain"},{"name":"Hospital del Mar Research Institute, Barcelona, Spain.  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