Amyloid-Associated Depression—or Not?

Abstract

In the current issue of Biological Psychiatry, Mackin et al. ( 1 Mackin R.S. Insel P.S. Landau S. Bickford D. Morin R. Rhodes E. et al. Late-life depression is associated with reduced cortical amyloid burden: Findings from the Alzheimer’s Disease Neuroimaging Initiative Depression Project. Biol Psychiatry. 2021; 89: 757-765 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar ) throw new light on the relationship between amyloid-β (Aβ) and depression in older individuals without dementia. But they may also compel us to throw some of our previous assumptions about this emerging field out the window. Early evidence for a link between late-life depression (LLD) and elevated Aβ pathogenesis came from postmortem studies of patients with dementia revealing an association between Aβ plaques and a history of major depression ( 2 Rapp M.A. Schnaider-Beeri M. Grossman H.T. Sano M. Perl D.P. Purohit D.P. et al. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry. 2006; 63: 161-167 Crossref PubMed Scopus (294) Google Scholar ). The advent of positron emission tomography (PET) enabled the study of clinicopathologic associations in vivo and provided further support for Aβ pathogenesis as a possible mechanism underlying the connection between LLD and Alzheimer’s disease (AD). Elevated cortical Aβ deposition in older individuals with current or lifetime major depression has been observed in most PET studies ( 3 Kumar A. Kepe V. Barrio J.R. Siddarth P. Manoukian V. Elderkin-Thompson V. et al. Protein binding in patients with late-life depression. Arch Gen Psychiatry. 2011; 68: 1143-1150 Crossref PubMed Scopus (60) Google Scholar , 4 Wu K.Y. Hsiao I.T. Chen C.S. Chen C.H. Hsieh C.J. Wai Y.Y. et al. Increased brain amyloid deposition in patients with a lifetime history of major depression: Evidenced on 18F-florbetapir (AV-45/Amyvid) positron emission tomography. Eur J Nucl Med Mol Imaging. 2014; 41: 714-722 Crossref PubMed Scopus (76) Google Scholar ). Longitudinal cohort studies using PET imaging have also reported positive associations between Aβ pathology and subsyndromal depressive symptoms in cognitively normal older adults ( 5 Krell-Roesch J. Lowe V.J. Neureiter J. Pink A. Roberts R.O. Mielke M.M. et al. Depressive and anxiety symptoms and cortical amyloid deposition among cognitively normal elderly persons: The Mayo Clinic Study of Aging. Int Psychogeriatr. 2018; 30: 245-251 Crossref PubMed Scopus (34) Google Scholar , 6 Donovan N.J. Locascio J.J. Marshall G.A. Gatchel J. Hanseeuw B.J. Rentz D.M. et al. Longitudinal association of amyloid beta and anxious-depressive symptoms in cognitively normal older adults. Am J Psychiatry. 2018; 175: 530-537 Crossref PubMed Scopus (106) Google Scholar ). Of note, also in this issue of Biological Psychiatry, Xu et al. ( 7 Xu W. Feng W. Shen X.-N. Bi Y.-L. Ma Y.-H. Li J.-Q. et al. Amyloid pathologies modulate the associations of minimal depressive symptoms with cognitive impairments in older adults without dementia. Biol Psychiatry. 2021; 89: 766-775 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ) corroborate these findings in older adults without dementia and use causal mediation analyses to explore the mediation effects of AD pathologies on cognition. These authors thus provide important new evidence that the influence of minimal depressive symptoms on cognition is partially mediated by Aβ pathology and that the causal relationship between depression and Aβ might be bidirectional. SEE CORRESPONDING ARTICLE ON PAGE 757 SEE CORRESPONDING ARTICLE ON PAGE 757 Late-Life Depression Is Associated With Reduced Cortical Amyloid Burden: Findings From the Alzheimer’s Disease Neuroimaging Initiative Depression ProjectBiological PsychiatryVol. 89Issue 8PreviewWe evaluated the role of cortical amyloid deposition as a factor contributing to memory dysfunction and increased risk of dementia associated with late-life depression (LLD). Full-Text PDF