IMPORTANCE: Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. OBJECTIVE: To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. MAIN OUTCOMES AND MEASURES: Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. RESULTS: In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. CONCLUSIONS AND RELEVANCE: Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

1st Department of Neurology Aiginition Hospital National and Kapodistrian University of Athens Medical School Athens Greece

Ace Alzheimer Center Barcelona Universitat Internacional de Catalunya Barcelona Spain

Aix Marseille University L'Assistance publique Hôpitaux de Marseille Centre National de la Recherche Scientifique Centrale Marseille Institut Fresnel Timone Hospital Centre Européen de Recherche en Imagerie Médicale Nuclear Medicine Department Marseille France

Aix Marseille University National Institute of Health and Medical Research Neurosciences des Systèmes Marseille France

Alzheimer's Centre Reina Sofia Fundación Centro de Investigación de Enfermedades Neurológicas Carlos 3 Institute of Health Madrid Spain

Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Service Hospital Clínic of Barcelona August Pi i Sunyer Biomedical Research Institute Barcelona Spain

Applied Biology Council of Scientific and Industrial Research Indian Institute of Chemical Technology Hyderabad Telangana State India

Assitance Publique des Hopitaux de Marseille Timone Service de Neurologie et Neuropsychologie Hôpital Timone Adultes Marseille France

Banner Alzheimer's Institute Phoenix Arizona

Center for Alzheimer Research and Treatment Department of Neurology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts

Center for Neuroscience and Cell Biology Centre for Innovative Biomedicine and Biotechnology University of Coimbra Coimbra Portugal

Center for Research and Advanced Therapies Cita Alzheimer Foundation Donostia San Sebastian Spain

Center for Vital Longevity School of Behavioral and Brain Sciences The University of Texas at Dallas Richardson

Center of Neurology Department of Neurodegeneration and Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany

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

Centro Disturbi della Memoria Laboratorio di Neurochimica Clinica Clinica Neurologica Università di Perugia Perugia Italy

Charité Universitätsmedizin Berlin Campus Benjamin Franklin Berlin Deutschland

Clinic for Neurogeriatrics and Neurological Rehabilitation University and Rehabilitation Hospital Ulm Ulm Germany

Clinical Memory Research Unit Department of Clinical Sciences Lund University Lund Sweden

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Cognitive Disorder Research Unit Department of Clinical Sciences Malmö Sweden

Cognitive Medicine Unit Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Danish Dementia Research Center Department of Neurology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Biochemical Diagnostics University Hospital of Białystok Białystok Poland

Department of Biochemistry Kakatiya Medical College Mahatma Gandhi Memorial Hospital Warangal Telangana State India

Department of Biochemistry Postgraduate Institute of Medical Education and Research Chandigarh India

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Biomedical and Pharmaceutical Sciences College of Pharmacy The University of Rhode Island Kingston

Department of Biomedical Sciences University of Antwerp Antwerp Belgium

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Electrical Engineering Eindhoven University of Technology Eindhoven the Netherlands

Department of Epidemiology Biogen Cambridge Massachusetts

Department of Geriatric Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

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

Department of Geriatrics Turku University Hospital Wellbeing Services County of Southwestern Finland Turku Finland

Department of Geriatrics University of Goettingen Medical School Goettingen Germany

Department of Head and Skin Ghent Experimental Psychiatry Lab Faculty of Medicine and Health Sciences Ghent University Ghent Belgium

Department of Health Sciences University of Genoa Genoa Italy

Department of Internal Medicine and Gerontology Faculty of Medicine Jagiellonian University Medical College Krakow Poland

Department of Neurobiology Care Sciences and Society Division of Clinical Geriatrics Karolinska Institutet Center for Alzheimer Research Stockholm Sweden

Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden

Department of Neurodegeneration Diagnostics Medical University of Białystok Białystok Poland

Department of Neurodegenerative Disease University College London Queen Square Institute of Neurology London United Kingdom

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

Department of Neurology Akershus University Hospital Lorenskog Norway

Department of Neurology Alzheimer Centre Amsterdam Amsterdam Neuroscience Amsterdam University Medical Centers location Vrije Universiteit Medical Center Amsterdam Amsterdam the Netherlands

Department of Neurology and the Alzheimer's Disease Research Center Washington University School of Medicine St Louis Missouri

Department of Neurology Columbia University New York City New York

Department of Neurology Institut de la Mémoire et de la Maladie d'Alzheimer Centre de Référence Démences Rares Hôpital de la Pitié Salpêtrière Assistance Publique Hôpitaux de Paris Paris France

Department of Neurology Institute of Clinical Medicine University of Eastern Finland Kuopio Finland

Department of Neurology Mayo Clinic in Florida Jacksonville

Department of Neurology Nehru Hospital Postgraduate Institute of Medical Education and Research Chandigarh India

Department of Neurology of Memory and Language Groupe Hospitalier Universitaire Paris Psychiatry and Neurosciences Hôpital Sainte Anne Paris France

Department of Neurology Onze Lieve Vrouw Hospital Aalst Belgium

Department of Neurology Osaka Metropolitan University Graduate School of Medicine Osaka Japan

Department of Neurology University Hospital of Munich Munich Germany

Department of Neurology University Hospital of North Norway Tromsø Norway

Department of Neurosciences Rehabilitation Ophthalmology and Maternal Fetal Medicine University of Genoa Genoa Italy

Department of Nuclear Medicine Faculty of Medicine and University Hospital Cologne University of Cologne Germany

Department of Nuclear Medicine Klinikum Bayreuth Bayreuth Germany

Department of Nuclear Medicine Klinikum rechts der Isar Technical University of Munich Munich Germany

Department of Nuclear Medicine Marqués de Valdecilla University Hospital and Instituto de Investigación Marqués de Valdecilla Santander Spain

Department of Nuclear Medicine Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Nutrition and Diatetics Harokopio University Kallithea Athens Greece

Department of Old Age Psychiatry Psychology and Neuroscience King's College London United Kingdom

Department of Pathology and Immunology Department of Neurology Washington University School of Medicine Saint Louis Missouri

Department of Psychiatry and Human Behavior Alpert Medical School of Brown University Providence Rhode Island

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

Department of Psychiatry and Neuropsychology Alzheimer Center Limburg School for Mental Health and Neuroscience Maastricht University Maastricht the Netherlands

Department of Psychiatry and Psychotherapy Klinikum rechts der Isar Technical University of Munich School of Medicine and Health Munich Germany

Department of Psychiatry and Psychotherapy Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Department of Psychiatry and Psychotherapy University Hospital Friedrich Alexander University Erlangen Nuremberg Erlangen Germany

Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Germany

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

Department of Psychiatry Cognition and Old Age Psychiatry Sahlgrenska University Hospital Västra Götalandsregion Sweden

Department of Psychiatry Faculty of Medicine McGill University Montreal Quebec Canada

Department of Psychiatry Seoul National University College of Medicine Seoul Republic of Korea

Department of Psychology The Arctic University of Norway Tromsø Norway

Department of Psychology University of Gothenburg Gothenburg Sweden

Department of Radiation Oncology Emory University Atlanta Georgia

Department of Radiology Massachusetts General Hospital Boston

Department of Radiology University Medical Center Leiden Leiden the Netherlands

Departments of Neurology and Psychiatry and Bru BRAIN Universitair Ziekenhuis Brussel Brussels Belgium

Douglas Mental Health University Institute Montreal Quebec Canada

Epidemiology and Data Science Vrije Universiteit Amsterdam Amsterdam University Medical Centers location Vrije Universiteit Medical Center Amsterdam the Netherlands

Excellence Center for Memory Diseases Brain Health and Longevity Medicine Ana Aslan International Foundation Bucharest Romania

Faculty of Medicine and Pharmacy Vrije Universiteit Brussel Brussels Belgium

Faculty of Medicine University of Coimbra Coimbra Portugal

Faculty of Medicine University of Lisbon Lisboa Portugal

Geriatrics Gerontology and Old Age Psychiatry Clinical Department Carol Davila University of Medicine and Pharmacy Elias Emergency Clinical Hospital Bucharest Romania

German Center for Neurodegenerative Diseases Bonn Cologne Germany

German Center for Neurodegenerative Diseases Munich Germany

Graduate School of Medicine and Faculty of Medicine The University of Tokyo Tokyo Japan

Harvard Aging Brain Study Department of Neurology Harvard Medical School Boston Massachusetts

Helen Wills Neuroscience Institute University of California Berkeley

Hong Kong Center for Neurodegenerative Diseases Hong Kong China

Institute of Human Behavioral Medicine Medical Research Center Seoul National University Seoul Republic of Korea

Institute of Neuroscience and Medicine Molecular Organization of the Brain Forschungszentrum Jülich Jülich Germany

Istituto delle Scienze Neurologiche di Bologna Scientific Institute for Research Hospitalization and Healthcare Bologna Italy

Klinikum Bremen Ost University of Oldenburg Institute of Psychology Oldenburg Germany

McConnell Brain Imaging Centre Montreal Neurological Institute Montreal Quebec Canada

Memory Clinic University Hospitals and University of Geneva Geneva Switzerland

Memory Unit Neurology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain

Munich Cluster for Systems Neurology Munich Germany

National and Kapodistrian University of Athens School of Medicine 1st Department of Neurology Eginition Hospital Athens Greece

Neurocenter Department of Neurology Kuopio University Hospital Kuopio Finland

Neurochemistry Lab Department of Laboratory Medicine Amsterdam Neuroscience Amsterdam University Medical Centers location Vrije Universiteit Medical Center Amsterdam the Netherlands

Neurology Department and Laboratory of Neurochemistry Centro Hospitalar e Universitário de Coimbra Coimbra Portugal

Neurology Department Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Sanitaria Valdecilla University of Cantabria Santander Biomedical Research Networking Center on Neurodegenerative Diseases Madrid Santander Spain

Neurology Unit Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Neuropsychiatric Epidemiology Unit Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

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

Ospedale Policlinico San Martino Scientific Institute for Research Hospitalization and Healthcare Genoa Italy

Paris Saclay University BioMaps Inserm Commissariat à l'énergie atomique et aux énergies alternatives Service Hospitalier Frederic Joliot Orsay France

Paris Saclay University Research Unit in Clinical and Translational Applicative NeuroImaging Neurospin Commissariat à l'énergie atomique et aux énergies alternatives Gif sur Yvette France

School of Medical Sciences Örebro University Örebro Sweden

Translational Neuroscience Laboratory McLean Hospital Harvard Medical School Belmont Massachusetts

Turku Positron Emission Tomography Centre University of Turku Turku Finland

United Kingdom Dementia Research Institute London United Kingdom

Vrije Universiteit Brussel Center for Neurosciences Neuroprotection and Neuromodulation Research Group Brussels Belgium

Wisconsin Alzheimer's Disease Research Center University of Wisconsin School of Medicine and Public Health University of Wisconsin Madison Madison

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