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It has been well established that parieto-temporal hypometabolism on FDG-PET is closely associated with medial temporal atrophy on MRI in Alzheimer\u2019s disease. Substantial biological heterogeneity, expressed as distinct subtypes of hypometabolism or atrophy patterns, has been previously described in Alzheimer\u2019s disease using data-driven and hypothesis-driven methods. However, the link between these two imaging modalities has not yet been explored in the context of Alzheimer\u2019s disease subtypes. To investigate this link, the current study utilized FDG-PET and MRI scans from 180 amyloid-beta positive Alzheimer\u2019s disease dementia patients, 339 amyloid-beta positive mild cognitive impairment and 176 amyloid-beta negative cognitively normal controls from the Alzheimer\u2019s Disease Neuroimaging Initiative. Random forest hierarchical clustering, a data-driven model for identifying subtypes, was implemented in the two modalities: one with standard uptake value ratios and the other with grey matter volumes. Five hypometabolism- and atrophy-based subtypes were identified, exhibiting both cortical-predominant and limbic-predominant patterns although with differing percentages and clinical presentations. Three cortical-predominant hypometabolism subtypes found were Cortical Predominant (32%), Cortical Predominant+ (11%) and Cortical Predominant posterior (8%), and two limbic-predominant hypometabolism subtypes found were Limbic Predominant (36%) and Limbic Predominant frontal (13%). In addition, little atrophy (minimal) and widespread (diffuse) neurodegeneration subtypes were observed from the MRI data. The five atrophy subtypes found were Cortical Predominant (19%), Limbic Predominant (27%), Diffuse (29%), Diffuse+ (6%) and Minimal (19%). Inter-modality comparisons showed that all FDG-PET subtypes displayed medial temporal atrophy, whereas the distinct MRI subtypes showed topographically similar hypometabolic patterns. Further, allocations of FDG-PET and MRI subtypes were not consistent when compared at an individual level. Additional analysis comparing the data-driven clustering model with prior hypothesis-driven methods showed only partial agreement between these subtyping methods. FDG-PET subtypes had greater differences between limbic-predominant and cortical-predominant patterns, and MRI subtypes had greater differences in severity of atrophy. In conclusion, this study highlighted that Alzheimer\u2019s disease subtypes identified using both FDG-PET and MRI capture distinct pathways showing cortical versus limbic predominance of neurodegeneration. However, the subtypes do not share a bidirectional relationship between modalities and are thus not interchangeable.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae426","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T15:22:36Z","timestamp":1732202556000},"source":"Crossref","is-referenced-by-count":6,"title":["Divergent neurodegenerative patterns: Comparison of [18F] fluorodeoxyglucose-PET- and MRI-based Alzheimer\u2019s disease subtypes"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-1954","authenticated-orcid":false,"given":"Sophia H","family":"Wheatley","sequence":"first","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet , 171 77 Stockholm ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6499-1251","authenticated-orcid":false,"given":"Rosaleena","family":"Mohanty","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet , 171 77 Stockholm ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6600-8086","authenticated-orcid":false,"given":"Konstantinos","family":"Poulakis","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet , 171 77 Stockholm ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fedor","family":"Levin","sequence":"additional","affiliation":[{"name":"Deutsches Zentrum f\u00fcr Neurodegenerative Erkrankungen (DZNE) , 18147 Rostock ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Sebastian","family":"Muehlboeck","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet , 171 77 Stockholm ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agneta","family":"Nordberg","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet , 171 77 Stockholm ,","place":["Sweden"]},{"name":"Theme Inflammation and Aging, Karolinska University Hospital , 171 76 Stockholm ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel J","family":"Grothe","sequence":"additional","affiliation":[{"name":"Reina Sofia Alzheimer Centre, CIEN Foundation, ISCIII , 28031 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9522-4338","authenticated-orcid":false,"given":"Daniel","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet , 171 77 Stockholm ,","place":["Sweden"]},{"name":"Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias , 35016 Las Palmas ,","place":["Espa\u00f1a"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3115-2977","authenticated-orcid":false,"given":"Eric","family":"Westman","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet , 171 77 Stockholm 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