The association of diabetes with Alzheimer's disease biomarkers and vascular burden across European aging and memory clinic cohorts

  • Veerle van Gils*
  • , Willemijn J. Jansen
  • , Wiesje M. van der Flier
  • , Pablo Martinez-Lage
  • , Jakub Hort
  • , Inez H. G. B. Ramakers
  • , Olivier Rouaud
  • , Markku Laakso
  • , Sebastiaan Engelborghs
  • , Julius Popp
  • , Alberto Lleó
  • , Anders Wallin
  • , Magda Tsolaki
  • , Charlotte E. Teunissen
  • , Rik Vandenberghe
  • , Yvonne Freund-Levi
  • , Lutz Frölich
  • , Henrik Zetterberg
  • , Johannes Streffer
  • , Simon Lovestone
  • Justine Moonen, Argonde van Harten, Katerina Veverová, Nienke Legdeur, Anouk den Braber, Daniel Damian, Anette Hall, Janita Bralten, Giuseppe Fanelli, Barbara Franke, Geert Poelmans, Monica Bulló, Susana Jimenez-Murcia, Fernando Fernandez-Aranda, Jordi Salas-Salvadó, Søren Dalsgaard, Pieter Jelle Visser, Stephanie J. B. Vos
*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

INTRODUCTION: It remains unclear whether diabetes mellitus (DM) is associated with Alzheimer's disease (AD) pathology and associated vascular burden. METHODS: We included cognitively normal (CN), mild cognitive impairment (MCI), and dementia individuals. We assessed associations between DM and AD biomarkers (amyloid beta [Aβ], phosphorylated tau-181 [p-tau181], total tau [t-tau], and medial temporal atrophy [MTA]) and vascular burden (white matter hyperintensities, microbleeds) by logistic regression. Secondary analyses assessed associations between DM and profiles of Aβ combined with p-tau181/t-tau/MTA/white matter hyperintensity/microbleeds. RESULTS: We included 5550 participants (65.8+-8.7 years, 8.7% DM). DM was associated with lower odds of abnormal AD biomarkers: Aβ in MCI (odds ratio [OR] = 0.70, 95% confidence interval [CI]: 0.51–0.95, p = 0.02) and dementia (OR = 0.44, 0.26–0.78, p = 0.003), and p-tau181 in dementia (OR = 0.64, 0.41–1.00, p = 0.045). Secondary analyses indicated associations of DM with abnormal t-tau (OR = 1.57, 1.00–2.46, p = 0.048) and MTA (OR = 1.96, 1.05–3.68, p = 0.04) only in CN individuals with normal Aβ. DISCUSSION: In cognitively impaired individuals, DM was associated with lower odds of Aβ pathology, whereas DM was associated with neurodegeneration markers in CN individuals without Aβ pathology. Highlights: Diabetes mellitus (DM) was associated with lower odds of amyloid beta (Aβ) and phosphorylated tau (p-tau) pathology across clinical populations. DM was associated with total tau and medial temporal atrophy in cognitively normal individuals without Aβ pathology. DM may be associated with dementia through neurodegenerative pathways other than Alzheimer's disease.
Original languageEnglish
Article numbere70804
JournalAlzheimer's and Dementia
Volume21
Issue number10
DOIs
Publication statusPublished - 1 Oct 2025

Funding

The authors are grateful to all cohorts that contributed to this study by sharing their data with us: Amsterdam Dementia Cohort (ADC; involving W.V.D.F., J.M., and A.V.H.), BioBank Alzheimer Center Limburg (BB-ACL; involving I.R.), EMIF Preclin-AD and EMIF 90+ (involving N.L. and A.D.B.), Czech Brain Aging Study (CBAS; involving J.H. and K.V.), Gipuzkoa Alzheimer Project (GAP; involving P.M.L.), CLEMENS (involving O.R. and D.D.), and Metabolic Syndrome in Men (METSIM; involving M.L. and A.H.). In addition, data used in preparation of this article were obtained from the Longitudinal Cohort Study (LCS), delivered by the European Prevention of Alzheimer's Disease (EPAD) Consortium. As such investigators within the EPAD LCS and EPAD Consortium contributed to the design and implementation of EPAD and/or provided data but did not participate in the analysis or writing of this report. A complete list of EPAD Investigators can be found at: http://ep-ad.org/wp-content/uploads/2020/12/202010_List-of-epadistas.pdf. Data also involved consortium data from European Medical Information Framework (EMIF) Multimodal Biomarker Discovery Study (MBD) (involving S.E., J.P., A.L., A.W., M.T., C.E.T., R.V., Y.F.L., L.F., H.Z., J.S., and S.L.). We would also like to thank the H2020 PRIME consortium (involving V.V.G., W.J.J., J.B., G.F., B.F., G.P., M.B., S.J.M., F.F.A., J.S.S., S.D., P.J.V., and S.B.), especially work package 1, for their valuable support and contributions. This research was supported by funding from the European Community's Horizon H2020/2014 - 2020 under grant agreement no. 847879 (PRIME). The content of the paper is solely the responsibility of the authors and does not necessarily represent the official views of the European Commission. This work used data and/or samples from the EPAD project, which received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking EPAD grant agreement no. 115736 and an Alzheimer's Association Grant (SG21-818099-EPAD). 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), National MS Society (Progressive MS alliance), Alzheimer's Drug Discovery Foundation, Alzheimer's Association, Health Holland, the Dutch Research Council (ZonMw), The Selfridges Group Foundation, and Alzheimer Netherlands. C.E.T. 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). C.E.T. is recipient of TAP-dementia, a a ZonMw-funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018 and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer's Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). M.B. received the ICREA Academy 2023 Distinction from the Autonomous Government of Catalonia. G.P. is director and chief scientific officer of Drug Target ID, Ltd., but activities at this company do not constitute competing interests regarding this paper. 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, and Vivoryon. She is Editor‐in‐Chief of , and serves on editorial boards of /Springer, and . She had consultancy/speaker contracts with Eli Lilly, Merck, Novo Nordisk, Olink, and Roche. B.F. has received educational speaking fees and travel support from Medice. H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). S.L. currently works at Johnson & Johnson. F.F.A. and S.J.M. have been consultants/speakers for NovoNordisk. P.J.V. received grants from Innovative Medicine Initiative, ZonMw, and Biogen. All other authors have nothing to disclose. Author disclosures are available in the Supporting Information . Alzheimer's Research & Therapy Medidact Neurologie Neurology: Neuroimmunology & Neuroinflammation The authors are grateful to all cohorts that contributed to this study by sharing their data with us: Amsterdam Dementia Cohort (ADC; involving W.V.D.F., J.M., and A.V.H.), BioBank Alzheimer Center Limburg (BB‐ACL; involving I.R.), EMIF Preclin‐AD and EMIF 90+ (involving N.L. and A.D.B.), Czech Brain Aging Study (CBAS; involving J.H. and K.V.), Gipuzkoa Alzheimer Project (GAP; involving P.M.L.), CLEMENS (involving O.R. and D.D.), and Metabolic Syndrome in Men (METSIM; involving M.L. and A.H.). In addition, data used in preparation of this article were obtained from the Longitudinal Cohort Study (LCS), delivered by the European Prevention of Alzheimer's Disease (EPAD) Consortium. As such investigators within the EPAD LCS and EPAD Consortium contributed to the design and implementation of EPAD and/or provided data but did not participate in the analysis or writing of this report. A complete list of EPAD Investigators can be found at: http://ep‐ad.org/wp‐content/uploads/2020/12/202010_List‐of‐epadistas.pdf . Data also involved consortium data from European Medical Information Framework (EMIF) Multimodal Biomarker Discovery Study (MBD) (involving S.E., J.P., A.L., A.W., M.T., C.E.T., R.V., Y.F.L., L.F., H.Z., J.S., and S.L.). We would also like to thank the H2020 PRIME consortium (involving V.V.G., W.J.J., J.B., G.F., B.F., G.P., M.B., S.J.M., F.F.A., J.S.S., S.D., P.J.V., and S.B.), especially work package 1, for their valuable support and contributions. This research was supported by funding from the European Community's Horizon H2020/2014 ‐ 2020 under grant agreement no. 847879 (PRIME). The content of the paper is solely the responsibility of the authors and does not necessarily represent the official views of the European Commission. This work used data and/or samples from the EPAD project, which received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking EPAD grant agreement no. 115736 and an Alzheimer's Association Grant (SG21‐818099‐EPAD). 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), National MS Society (Progressive MS alliance), Alzheimer's Drug Discovery Foundation, Alzheimer's Association, Health Holland, the Dutch Research Council (ZonMw), The Selfridges Group Foundation, and Alzheimer Netherlands. C.E.T. 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). C.E.T. is recipient of TAP‐dementia, a a ZonMw‐funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023‐00356; #2022‐01018 and #2019‐02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG‐71320), the Alzheimer's Drug Discovery Foundation (ADDF), USA (#201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF‐21‐831376‐C, #ADSF‐21‐831381‐C, #ADSF‐21‐831377‐C, and #ADSF‐24‐1284328‐C), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling‐Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022‐0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021‐00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI‐1003). M.B. received the ICREA Academy 2023 Distinction from the Autonomous Government of Catalonia.

FundersFunder number
Dutch National Dementia Strategy
H2020 Marie Skłodowska-Curie Actions
Health Holland
Erling-Perssons Stiftelse
EPND
Metabolic Syndrome in Men
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Czech Brain Aging Study
Bluefield Project
Selfridges Group Foundation
National Multiple Sclerosis Society
Generalitat de Catalunya
National Institute for Health and Care Research
European Prevention of Alzheimer's Disease
Innovative Medicine Initiative
European Community's Horizon H2020/2014 - 2020
Horizon 2020 Framework Programme
European Community's Horizon H2020
Olav Thon Stiftelsen
Institució Catalana de Recerca i Estudis Avançats
Cure Alzheimer's Fund
Biogen
BioBank Alzheimer Center Limburg
AD Strategic Fund
Gipuzkoa Alzheimer Project
Alzheimer's AssociationSG21‐818099‐EPAD
Familjen Rönströms Stiftelse#FO2022‐0270
ZonMw73305095007, 10510032120003
European Commission860197, 101053962, 201809‐2016862, 71320, 831434
UK Dementia Research InstituteUKDRI‐1003
EU Joint Programme – Neurodegenerative Disease ResearchJPND2021‐00694
Vetenskapsrådet2019‐02397, 2023‐00356, 2022‐01018
2014 ‐ 2020847879
European Federation of Pharmaceutical Industries and Associations115736
IMI101034344
Alzheimer's Drug Discovery Foundation201809-2016862

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