Depressive Symptoms and Amyloid Pathology
Authors: Wiels Wietse A. , Oomens Julie E. , Engelborghs Sebastiaan , Baeken Chris , von Arnim Christine A.F. , Boada Mercè , Didic Mira , Dubois Bruno , Fladby Tormod , van der Flier Wiesje M. , Frisoni Giovanni B. , Fröhlich Lutz , Gill Kiran Dip , Grimmer Timo , Hildebrandt Helmut , Hort Jakub , Itoh Yoshiaki , Iwatsubo Takeshi , Klimkowicz-Mrowiec Aleksandra , Lee Dong Young , Lleó Alberto , Martinez-Lage Pablo , de Mendonça Alexandre , Meyer Philipp T. , Kapaki Elisabeth N. , Parchi Piero , Pardini Matteo , Parnetti Lucilla , Popp Julius , Rami Lorena , Reiman Eric M. , Rinne Juha O. , Rodrigue Karen M. , Sánchez-Juan Pascual , Santana Isabel , Sarazin Marie , Scarmeas Nikolaos , Skoog Ingmar , Snyder Peter J. , Sperling Reisa A. , Villeneuve Sylvia , Wallin Anders , Wiltfang Jens , Zetterberg Henrik , Ossenkoppele Rik , Verhey Frans R. J. , Vos Stephanie J. B. , Visser Pieter Jelle , Jansen Willemijn J. ,   Amyloid Biomarker Study group,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), the A4 Study group, Dominantly Inherited Alzheimer Network (DIAN), European Prevention of Alzheimer’s Dementia (EPAD) consortium, Fundació ACE Healthy Brain Initiative (FACEHBI), Harvard Aging Brain Stud, Alcolea Daniel , Altomare Daniele , Baiardi Simone , Baldeiras Ines , Bateman Randall J. , Blennow Kaj , Bottlaender Michel , den Braber Anouk , van Buchem Mark A. , Byun Min Soo , Cerman Jiří , Chen Kewei , Chipi Elena , Day Gregory S. , Drzezga Alexander , Eckerström Marie , Ekblad Laura L. , Epelbaum Stéphane , Förster Stefan , Fortea Juan , Freund-Levi Yvonne , Frings Lars , Guedj Eric , Hausner Lucrezia , Hellwig Sabine , Huey Edward D. , Jiménez-Bonilla Julio F. , Johnson Keith A. , Juaristi Ane Iriondo , Kandimalla Ramesh , Paraskevas George , Kern Silke , Kirsebom Bjørn-Eivind S. , Kornhuber Johannes , Lagarde Julien , Landau Susan M. , Legdeur Nienke , Llibre Guerra Jorge J. , Maserejian Nancy N. , Marquié Marta , Minatani Shinobu , Morbelli Silvia Daniela , Mroczko Barbara , Ntanasi Eva , de Oliveira Catarina Resende , Olivieri Pauline , Orellana Adelina , Perrin Richard J. , Peters Oliver , Prabhakar Sudesh , Ramakers Inez H. , Rodríguez-Rodriguez Eloy , Ruiz Agustín , Rüther Eckart , Selnes Per , Silva Dina , Soininen Hilkka , Spiru Luiza , Takeda Akitoshi , Teichmann Marc , Tijms Betty M. , Teunissen Charlotte E. , Thompson Loisa I. , Vogelgsangs Jonathan , Vöglein Jonathan , Waldemar Gunhild , Wallin Åsa K. , Yannakoulia Mary , Yi Dahyun , Zettergren Anna 
Published: January 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.