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Depressive Symptoms and Amyloid Pathology

Wiels, W.A. ; Ossenkoppele, R. LU and Jansen, W.J. (2025) In JAMA Psychiatry 82(3). p.296-310
Abstract
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... (More)
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. Copyright © 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies. (Less)
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keywords
Adult, Age Factors, Aged, Aged, 80 and over, Amyloid beta-Peptides, Apolipoprotein E4, Biomarkers, Cognitive Dysfunction, Cross-Sectional Studies, Depression, Female, Humans, Male, Middle Aged, Peptide Fragments, Positron-Emission Tomography, amyloid beta protein, amyloid beta-protein (1-42), apolipoprotein E4, biological marker, peptide fragment, adult, age, aged, cerebrospinal fluid, cognitive defect, cross-sectional study, depression, female, genetics, human, male, metabolism, middle aged, positron emission tomography, very elderly
in
JAMA Psychiatry
volume
82
issue
3
pages
15 pages
publisher
American Medical Association
external identifiers
  • scopus:85217865988
  • pmid:39841452
ISSN
2168-622X
DOI
10.1001/jamapsychiatry.2024.4305
language
English
LU publication?
yes
id
e91956c9-c6d0-498a-b984-4f6fdb105581
date added to LUP
2025-12-17 16:11:03
date last changed
2025-12-18 03:00:04
@article{e91956c9-c6d0-498a-b984-4f6fdb105581,
  abstract     = {{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.  Copyright © 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.}},
  author       = {{Wiels, W.A. and Ossenkoppele, R. and Jansen, W.J.}},
  issn         = {{2168-622X}},
  keywords     = {{Adult; Age Factors; Aged; Aged, 80 and over; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Depression; Female; Humans; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; amyloid beta protein; amyloid beta-protein (1-42); apolipoprotein E4; biological marker; peptide fragment; adult; age; aged; cerebrospinal fluid; cognitive defect; cross-sectional study; depression; female; genetics; human; male; metabolism; middle aged; positron emission tomography; very elderly}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{296--310}},
  publisher    = {{American Medical Association}},
  series       = {{JAMA Psychiatry}},
  title        = {{Depressive Symptoms and Amyloid Pathology}},
  url          = {{http://dx.doi.org/10.1001/jamapsychiatry.2024.4305}},
  doi          = {{10.1001/jamapsychiatry.2024.4305}},
  volume       = {{82}},
  year         = {{2025}},
}