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View ORCID ProfileVikram Venkatraghavan, View ORCID ProfileDamiano Archetti, View ORCID ProfilePierrick Bourgeat, Chenyang Jiang, View ORCID ProfileMara ten Kate, Anna C. van Loenhoud, View ORCID ProfileRik Ossenkoppele, View ORCID ProfileCharlotte E. Teunissen, View ORCID ProfileElsmarieke van de Giessen, View ORCID ProfileYolande A.L. Pijnenburg, View ORCID ProfileGiovanni B. Frisoni, View ORCID ProfileBéla Weiss, View ORCID ProfileZoltán Vidnyánszky, View ORCID ProfileTibor Auer, View ORCID ProfileStanley Durrleman, View ORCID ProfileAlberto Redolfi, View ORCID ProfileSimon M. Laws, View ORCID ProfilePaul Maruff, Australian Imaging Biomarkers and Lifestyle Study, Alzheimer’s Disease Neuroimaging Initiative, E-DADS Consortium, View ORCID ProfileNeil P. Oxtoby, View ORCID ProfileAndre Altmann, View ORCID ProfileDaniel C. Alexander, View ORCID ProfileWiesje M. van der Flier, View ORCID ProfileFrederik Barkhof, View ORCID ProfileBetty M. Tijms
doi: https://doi.org/10.1101/2024.08.27.24312499
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Abstract
Background Previous studies reported on the existence of atrophy-based Alzheimer’s disease (AD) subtypes that associate with distinct clinical symptoms. However, the consistency of AD atrophy subtypes across approaches remains uncertain. This large-scale study aims to assess subtype concordance in individuals using two methods of data-driven subtyping.
Methods We included n = 10,011 patients across the clinical spectrum from 10 AD cohorts across Europe, regional volumes using Freesurfer v7.1.1. To characterise atrophy heterogeneity in the AD continuum, we introduced a hybrid two-step approach called Snowphlake (Staging NeurOdegeneration With PHenotype informed progression timeLine of biomarKErs) to identify subtypes and sequence of atrophy-events within each subtype. We compared our results with SuStaIn (Subtype and Stage Inference) which jointly estimates both, and was trained and validated similarly. The training dataset included Aβ+ participants (n = 1,195), and a control group of Aβ-cognitively unimpaired participants (n = 1,692). We validated model staging within each subtype, in a held-out clinical-validation dataset (n = 6,362) comprising patients across the clinical spectrum irrespective of Aβ biomarker status and an independent external dataset (n = 762). Furthermore, we validated the clinical significance of the detected subtypes, in a subset of Aβ+ validation datasets with n = 1,796 in the held-out sample and n = 159 in the external dataset. Lastly, we performed concordance analysis to assess the consistency between the methods.
Results In the AD dementia (AD-D) training data, Snowphlake identified four subtypes: diffuse cortical atrophy (21.1%, age 67.5 ± 9.3), parieto-temporal atrophy (19.8%, age 60.9 ± 7.9), frontal atrophy (24.8%, age 67.6 ± 8.8) and subcortical atrophy (25.1%, 68.3 ± 8.2). The subtypes assigned in Aβ+ validation datasets were associated with alterations in specific cognitive domains (Cohen’s f: [0.15 - 0.33]), while staging correlated with Mini-Mental State Examination (MMSE) scores (R: [-0.51 to - 0.28]) in the validation datasets. SuStaIn also identified four subtypes: typical (55.7%, age 66.7 ± 7.8), limbic-predominant (24.2%, age 72.2 ± 6.6), hippocampal-sparing (14.6%, age 62.8 ± 6.9), and subcortical (0.8%, age 68.2 ± 7.6). The subtypes assigned in Aβ+ validation datasets using SuStaIn were also associated with alterations in specific cognitive domains (Cohen’s f: [0.17 - 0.34]), while staging correlated with MMSE scores in the validation datasets (R: [-0.54 to - 0.26]). However, we observed low concordance between Snowphlake and SuStaIn, with 39.7% of AD-D patients consistently grouped in concordant subtypes by both the methods.
Conclusion In this multi-cohort study, both Snowphlake and SuStaIn identified four subtypes that were associated with different symptom profiles and atrophy-severity measures that were associated with global cognition. The low concordance between Snowphlake and SuStaIn suggests that heterogeneity may rather be a spectrum than discretised by subtypes.
Competing Interest Statement
F.B. is on the steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena. F.B. has been a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics and has research agreements with Merck, Biogen, GE Healthcare, Roche. F.B and D.C.A. are also co-founders and shareholders of Queen Square Analytics Ltd. N.P.O. is a consultant for Queen Square Analytics Ltd.Research programs of W.F. have been funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. W.F. holds the Pasman chair. W.F. is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). W.F. is recipient of TAP-dementia (www.tap-dementia.nl), receiving funding from ZonMw (#10510032120003). TAP-dementia receives co-financing from Avid Radiopharmaceuticals and Amprion. All funding is paid to her institution.W.F. has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. All funding is paid to her institution. W.F. is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. All funding is paid to her institution. W.F. participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. W.F. is member of the steering committee of EVOKE/EVOKE+ (NovoNordisk). All funding is paid to her institution. W.F. is member of the steering committee of PAVE, and Think Brain Health. W.F. was associate editor of Alzheimer, Research & Therapy in 2020/2021. W.F. is associate editor at Brain.C.E.T. has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Molecular Neurodegeneration, Neurology: Neuroimmunology & Neuroinflammation, Medidact Neurologie/Springer, and serves on committee to define guidelines for Cognitive disturbances, and one for acute Neurology in the Netherlands. She had consultancy/speaker contracts for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Eli Lilly, Merck, Novo Nordisk, Olink, Roche and Veravas.
Funding Statement
This study was supported by the Early Detection of Alzheimer's Disease Subtypes (E-DADS) project, an EU Joint Programme - Neurodegenerative Disease Research (JPND) project (see www.jpnd.eu). The project is supported under the aegis of JPND through the following funding organizations: United Kingdom, Medical Research Council (MR/T046422/1); Netherlands, ZonMW (733051106); France, Agence Nationale de la Recherche (ANR-19-JPW2-000); Italy, Italian Ministry of Health (MoH); Australia, National Health & Medical Research Council (1191535); Hungary, National Research, Development and Innovation Office (2019-2.1.7-ERA-NET-2020-00008).This work used the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-5353. W.F. and B.T. are recipients of TAP-dementia (www.tap-dementia.nl), receiving funding from ZonMw (#10510032120003). F.B. is supported by the NIHR biomedical research centre at UCLH. B.W. and Z.V. was supported by project no. RRF-2.3.1-21-2022-00015, which has been implemented with the support provided by the European Union. B.W. was also supported by project no. RRF-2.3.1-21-2022-00004 that has been implemented with the support of the European Union within the framework of the Artificial Intelligence National Laboratory.N.P.O. is supported by a UKRI Future Leaders Fellowship (UK Medical Research Council MR/S03546X/1). Research of C.E.T. is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE), European Partnership on Metrology, co-financed from the European Union's Horizon Europe Research and Innovation Programme and by the Participating States ((22HLT07 NEuroBioStand), CANTATE project funded by the Alzheimer Drug Discovery Foundation, Alzheimer Association, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CT is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). CT is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics committee/IRB of Amsterdam UMC, location VUmc gave ethical approval for this work.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Data Availability
The ADNI data used is this study were obtained from the ADNI database (adni.loni.usc.edu). The ADC data used in this study are available from the corresponding author, upon reasonable request. The AIBL imaging data used in this study were obtained from the AIBL LONI database (https://ida.loni.usc.edu/login.jsp?project=AIBL), while cognitive and genetic data can be requested from the AIBL management team, upon reasonable request by submitting an Expression of Interest (EOI) form available on the AIBL website (https://aibl.org.au/collaboration/). The NACC data used in this study were obtained from https://naccdata.org/. The OASIS data used in this study were obtained from https://sites.wustl.edu/oasisbrains/website. The data of the other cohorts used in this study can be requested from the neuGRID (https://www.neugrid2.eu/) and GAAIN (https://www.gaain.org) platforms after registration.
Copyright
The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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PostedAugust 28, 2024.
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