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.

1st Department of Neurology School of Medicine Faculty of Health Sciences Aristotle University of Thessaloniki Makedonia Thessaloniki Greece

Alzheimer Center and Department of Neurology Amsterdam Neuroscience Campus VU University Medical Center Amsterdam Netherlands

Alzheimer Center Limburg Mental Health and Neuroscience Research Institute Maastricht University Maastricht Netherlands

Amsterdam Neuroscience Neurodegeneration Amsterdam The Netherlands

Center of Environmental Food and Toxicological Technology TecnATox Rovira i Virgili University Tarragona Spain

Charles University 2nd Faculty of Medicine Motol University Hospital Prague Czech Republic

CHUV Lausanne Hospital Lausanne Switzerland

CIBER Fisiopatología Obesidad y Nutrición Instituto de Salud Carlos 3 Madrid Spain

CIBERNED Network Center for Biomedical Research in Neurodegenerative Diseases National Institute of Health Carlos 3 Madrid Spain

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Clinical Psychology Department University Hospital of Bellvitge Barcelona Spain

Department of Biochemistry and Biotechnology Rovira i Virgili University Reus Spain

Department of Biological Psychology Vrije Universiteit Amsterdam Amsterdam The Netherlands

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Biomedical Sciences University of Antwerp Antwerpen Belgium

Department of Clinical Sciences School of Medicine and Health Sciences University of Barcelona Barcelona Spain

Department of Geriatric Psychiatry University Hospital of Psychiatry Zürich and University of Zürich Zürich Switzerland

Department of Geriatric Psychiatry Zentralinstitut Für Seelische Gesundheit University of Heidelberg Mannheim Germany

Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands

Department of Neurobiology Care Sciences and Society Division of Neurogeriatrics Karolinska Institutet Stockholm Sweden

Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London UK

Department of Neurology Universitair Ziekenhuis Brussel and NEUR Research Group Center for Neurosciences Vrije Universiteit Brussel Brussels Belgium

Department of Psychiatry University of Oxford Warneford Hospital Oxford UK

Donders Institute for Brain Cognition and Behaviour Radboud University Nijmegen The Netherlands

Fundación CITA Alzhéimer Fundazioa Donostia Gipuzkoa Spain

Institute of Clinical Medicine University of Eastern Finland Kuopio Finland

Institute of Health Pere Virgili Avinguda del Doctor Josep Laporte Tarragona Spain

Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at University of Gothenburg Mölndal Sweden

Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry The Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Laboratory for Cognitive Neurology Department of Neurosciences Leuven Brain Institute Leuven Belgium

National Centre for Register based Research Department of Economics and Business School of Business and Social Sciences Aarhus University Aarhus Denmark

Neurochemistry Lab Department of Laboratory Medicine Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam The Netherlands

Neurology University Hospitals Leuven Leuven Belgium

Old Age Psychiatry Department of Psychiatry University Hospital of Lausanne Lausanne Switzerland

Psychoneurobiology of Eating and Addictive Behaviors Group Neurosciences Program Bellvitge Biomedical Research Institute Barcelona Spain

Reference Center for Biological Markers of Dementia Institute Born Bunge University of Antwerp Antwerp Belgium

Sant Pau Memory Unit Department of Neurology Institut d'Investigacions Biomèdiques Sant Pau Hospital de Sant Pau Universitat Autònoma de Barcelona Barcelona Spain

The Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH Aarhus Denmark

Translational Medicine Neuroscience UCB Biopharma SPRL Braine l'Alleud Belgium

UK Dementia Research Institute at UCL London UK

Unitat de Nutrició Humana ANUT DSM group Departament de Bioquímica i Biotecnologia Universitat Rovira i Virgili Sant Llorenç 21 Reus Spain

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