Depressive Symptoms and Amyloid Pathology
Authors: Wietse A. Wiels, Julie E. Oomens, Sebastiaan Engelborghs, Chris Baeken, Christine A.F. von Arnim, Mercè Boada, Mira Didic, Bruno Dubois, Tormod Fladby, Wiesje M. van der Flier, Giovanni B. Frisoni, Lutz Fröhlich, Kiran Dip Gill, Timo Grimmer, Helmut Hildebrandt, Jakub Hort, Yoshiaki Itoh, Takeshi Iwatsubo, Aleksandra Klimkowicz-Mrowiec, Dong Young Lee, Alberto Lleó, Pablo Martinez-Lage, Alexandre de Mendonça, Philipp T. Meyer, Elisabeth N. Kapaki, Piero Parchi, Matteo Pardini, Lucilla Parnetti, Julius Popp, Lorena Rami, Eric M. Reiman, Juha O. Rinne, Karen M. Rodrigue, Pascual Sánchez-Juan, Isabel Santana, Marie Sarazin, Nikolaos Scarmeas, Ingmar Skoog, Peter J. Snyder, Reisa A. Sperling, Sylvia Villeneuve, Anders Wallin, Jens Wiltfang, Henrik Zetterberg, Rik Ossenkoppele, Frans R. J. Verhey, Stephanie J. B. Vos, Pieter Jelle Visser, Willemijn J. Jansen, Daniel Alcolea, Daniele Altomare, Simone Baiardi, Ines Baldeiras, Randall J. Bateman, Kaj Blennow, Michel Bottlaender, Anouk den Braber, Mark A. van Buchem, Min Soo Byun, Jiří Cerman, Kewei Chen, Elena Chipi, Gregory S. Day, Alexander Drzezga, Marie Eckerström, Laura L. Ekblad, Stéphane Epelbaum, Stefan Förster, Juan Fortea, Yvonne Freund-Levi, Lars Frings, Eric Guedj, Lucrezia Hausner, Sabine Hellwig, Edward D. Huey, Julio F. Jiménez-Bonilla, Keith A. Johnson, Ane Iriondo Juaristi, Ramesh Kandimalla, George Paraskevas, Silke Kern, Bjørn-Eivind S. Kirsebom, Johannes Kornhuber, Julien Lagarde, Susan M. Landau, Nienke Legdeur, Jorge J. Llibre Guerra, Nancy N. Maserejian, Marta Marquié, Shinobu Minatani, Silvia Daniela Morbelli, Barbara Mroczko, Eva Ntanasi, Catarina Resende de Oliveira, Pauline Olivieri, Adelina Orellana, Richard J. Perrin, Oliver Peters, Sudesh Prabhakar, Inez H. Ramakers, Eloy Rodríguez-Rodriguez, Agustín Ruiz, Eckart Rüther, Per Selnes, Dina Silva, Hilkka Soininen, Luiza Spiru, Akitoshi Takeda, Marc Teichmann, Betty M. Tijms, Charlotte E. Teunissen, Loisa I. Thompson, Jonathan Vogelgsangs, Jonathan Vöglein, Gunhild Waldemar, Åsa K. Wallin, Mary Yannakoulia, Dahyun Yi, Anna Zettergren
Journal: JAMA Psychiatry (2025)

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.