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However, the development of biomarkers has enabled a shift towards in vivo biological definitions. There is now a need to characterize memory clinic populations using multi-dimensional biomarker information. Here, we employed a data-driven approach to develop a biological framework for categorizing individuals in a heterogeneous memory clinic cohort based on the presence, extent and sequence of several common pathologies.<\/jats:p>\n                  <jats:p>We studied 1677 individuals, including subjective cognitive decline (SCD, n = 255), mild cognitive impairment (MCI, n = 400), all cause dementia (n = 393) and cognitively normal controls (n = 625) from the BioFINDER-2 cohort [median age (interquartile range) = 72.0 (16.2) years; 50.3% female]. The Subtype and Stage Inference (SuStaIn) model was applied to biomarkers of amyloid-\u03b2 (A\u03b2) (CSF A\u03b242\/A\u03b240), tau (temporal meta-region of interest PET), neuronal \u03b1-synuclein [CSF seed amplification assay (SAA)], vascular pathology [MRI-based white matter hyperintensities (WMHs)] and regional atrophy (MRI-based cortical thickness) to identify biomarker-based clusters across the entire dataset. We then applied this framework to cognitively symptomatic individuals (n = 788) to compare clinical symptoms, disease progression rate and brain changes (atrophy and functional connectivity) across profiles.<\/jats:p>\n                  <jats:p>We identified five biomarker clusters reflecting established clinico-pathological entities, closely corresponding to (i) Alzheimer\u2019s disease [AD, n = 317 (40.2%)]; (ii) \u03b1-synuclein disease [\u03b1Syn, n = 123 (15.6%)]; (iii) vascular disease [Vascular, n = 67 (8.5%)]; (iv) mixed AD and Vascular [Mixed, n = 207 (26.3%)]; and (v) a heterogenous group of individuals characterized by atrophy without any of the major brain pathologies, here termed \u2018non-vascular, Alzheimer's, and synuclein pathology' [NOVAS, n = 74 (9.4%)]. The AD profile was characterized by global cognitive impairment and cortical atrophy in AD-associated regions. The \u03b1Syn profile was associated with visuospatial and executive dysfunction, motor impairment, hallucinations and functional connectivity disruptions throughout the brain, despite less overall atrophy compared to all others. The Vascular profile showed language and motor impairments, and both the Vascular and Mixed profiles demonstrated atrophy in cingulate and subcortical regions, alongside reduced periventricular white matter integrity. The NOVAS profile was older, demonstrated pronounced hippocampal and amygdala atrophy and baseline memory deficits, possibly reflecting neurodegenerative diseases for which currently no robust biomarkers are available, such as primary tauopathies and TDP-43 proteinopathies [e.g. limbic-predominant age-related TDP-43 encephalopathy (LATE)]. In longitudinal analyses, the AD profile showed the fastest global cognitive decline, while \u03b1Syn demonstrated an accelerated decline in language and executive and visuospatial functioning.<\/jats:p>\n                  <jats:p>To conclude, classifying individuals using a multimodal biomarker approach can provide valuable diagnostic and prognostic insights, with potential implications for clinical trials.<\/jats:p>","DOI":"10.1093\/brain\/awaf411","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T12:39:10Z","timestamp":1761568750000},"page":"1239-1253","source":"Crossref","is-referenced-by-count":6,"title":["Biological classification of memory clinic patients"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2759-9588","authenticated-orcid":false,"given":"Sophie E","family":"Mastenbroek","sequence":"first","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]},{"name":"Department of Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam University Medical Center location VUmc , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience , Brain imaging, Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyduine E","family":"Collij","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]},{"name":"Department of Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam University Medical Center location VUmc , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience , Brain imaging, Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toomas Erik","family":"Anij\u00e4rv","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Rittmo","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, SciLifeLab, Lund University , Lund 222 42 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra L","family":"Young","sequence":"additional","affiliation":[{"name":"UCL Hawkes Institute, Department of Computer Science, University College London , London WC1V 6LJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olof","family":"Strandberg","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7147-0112","authenticated-orcid":false,"given":"Ruben","family":"Smith","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , Malm\u00f6 205 02 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5404-8788","authenticated-orcid":false,"given":"Nicola","family":"Spotorno","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-1930","authenticated-orcid":false,"given":"Sebastian","family":"Palmqvist","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , Malm\u00f6 205 02 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-7724","authenticated-orcid":false,"given":"Niklas","family":"Mattsson-Carlgren","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , Malm\u00f6 205 02 ,","place":["Sweden"]},{"name":"Wallenberg Center for Molecular Medicine, Lund University , Lund 223 62 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shorena","family":"Janelidze","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-9524","authenticated-orcid":false,"given":"Piero","family":"Parchi","sequence":"additional","affiliation":[{"name":"IRCCS, Istituto Delle Scienze Neurologiche di Bologna (ISNB) , Bologna 40139 ,","place":["Italy"]},{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna , Bologna 40127 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob W","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, SciLifeLab, Lund University , Lund 222 42 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam University Medical Center location VUmc , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience , Brain imaging, Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Ossenkoppele","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]},{"name":"Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience , Neurodegeneration, Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8467-7286","authenticated-orcid":false,"given":"Oskar","family":"Hansson","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, Lund University , Lund 222 42 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"2026040804061324500_awaf411-B1","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1212\/WNL.34.7.939","article-title":"Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's 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