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Cortico-limbic volume abnormalities in late life depression are distinct from β amyloid and white matter pathologies

Molecular Psychiatry volume 30, pages 1267–1276 (2025)Cite this article

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Abstract

This study was conducted to clarify patterns of cortico-limbic volume abnormalities in late life depression (LLD) relative to non-depressed (ND) adults matched for amyloid β (Aβ) deposition and to evaluate the relationship of volume abnormalities with cognitive performance. Participants included 116 LLD and 226 ND. Classification accuracy of LLD status was estimated using area under the receiver operator characteristic curve. Twenty-one percent of LLD and ND participants were Aβ positive and the groups did not differ on white matter hyperintensity volume (WMH (logscale); β = 0.12, p = 0.28). Compared to ND, the LLD group exhibited significantly lower bilateral volume in the lateral orbitofrontal cortex, hippocampus, accumbens area, superior temporal lobe, temporal pole, and amygdala after multiple comparison correction (p < 0.009 for all). Cortico-limbic volumes significantly improved classification of LLD beyond demographic characteristics, Aβ status, and WMH (AUCVol = 0.71, AUCWMH, Aβ = 0.62, AUC difference, 0.09 [0.03 to 0.15]). LLD exhibited poorer performance on measures of global cognition, set shifting, and verbal learning and memory relative to ND. Cognitive function was positively associated with cortico-limbic volumes and these relationships did not differ by group. Secondary analyses with an ND sample additionally matched for Mild Cognitive Impairment (MCI) diagnosis showed a similar but attenuated pattern of volume abnormalities. Overall, our results support LLD as being associated with cortico-limbic volume abnormalities that are distinct from Aβ and white matter pathologies and that these volume abnormalities are important factors associated with cognitive dysfunction in LLD.

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Fig. 1
Fig. 2: Lower regional cortico-limbic volumes in late life depression (LLD) relative to non-depressed (ND) participants (N = 342).
Fig. 3: Association of demographic characteristics, white matter lesions, amyloid and cortico-limbic volumes with LLD classification (N = 342).
Fig. 4: Association of cognition with cortico-limbic volumes (N = 342).

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Data availability

De-identified data from participants who agreed to the distribution of data are available from the corresponding author upon reasonable request. Contact the corresponding author for more information.

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Acknowledgements

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Depression project (ADNI D) (National Institute of Mental Health Grant R01098062 and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). We acknowledge Ray and Dagmar Dolby Family Fund for research support and Avid Radiopharmaceuticals for providing Florbetapir for this study. Additional support was provided by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs (MKL, MTK, ER, RM). Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative-Depression project (ADNI-D) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) databases (www.loni .usc.edu). As such, the investigators within the ADNI D and ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. ADNI D investigators and ADNI investigators include http://adni.loni.usc.edu/study-design/ongoing-investigations/ ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., as well as non-profit partners the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation, with participation from the U.S. Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuroimaging at the University of California, Los Angeles.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA

    R. Scott Mackin, Emma Rhodes, Michelle Kassel, Maria Kryza-Lacombe, Emily Burns, David Bickford, Ruth Morin, Michael W. Weiner, Craig Nelson & Philip S. Insel

  2. Veterans Administration Medical Center, San Francisco, CA, USA

    R. Scott Mackin, Duygu Tosun & Michael W. Weiner

  3. Mental Illness Research Education and Clinical Centers, Veterans Administration Medical Center, San Francisco, CA, USA

    Emma Rhodes, Michelle Kassel, Maria Kryza-Lacombe & Ruth Morin

  4. Department of Radiology, University of California, San Francisco, CA, USA

    Duygu Tosun & Michael W. Weiner

  5. Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA

    Susan Landau

  6. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Meryl A. Butters

  7. University of Southern California, San Diego, CA, USA

    Paul Aisen & Rema Raman

  8. Alzheimer’s Therapeutic Research Institute, San Diego, CA, USA

    Paul Aisen & Rema Raman

  9. Indiana Alzheimer’s Disease Research Center and the Department of Radiology and Imaging Sciences University School of Medicine, Indianapolis, IN, USA

    Andrew J. Saykin

  10. Laboratory of Neuro Imaging, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Arthur Toga

  11. Department of Radiology, University of Michigan, Ann Arbor, MI, USA

    Robert Koeppe

  12. Mayo Clinic, Rochester, MN, USA

    Clifford Jack

  13. Department of Neurology, University of California, San Francisco, CA, USA

    Michael W. Weiner

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  1. R. Scott Mackin
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  2. Emma Rhodes
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Contributions

SM, PI, DB, RM, DT, SL, MB, PA, RR, AS, AT, CJ, MW, CN made substantial contributions to the design and conceptualization of the study. SM, ER, EB, DB, MB, SL, PA, RR, DT, RK, CJ, AS, RM, CN, PI acquired the data. PI, SM, CN analyzed and interpreted the data. SM drafted the manuscript. ER, MK, MKL, EB, DB, RM, DT, SL, MB, PA, RR, AS, AT, RK, CJ, MW, CN and PI critically reviewed and revised the manuscript and added important intellectual content.

Corresponding author

Correspondence to R. Scott Mackin.

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Competing interests

During the past 2 years, RSM has received research support from The National Institute of Mental Health, the National Institute of Aging, and Johnson and Johnson. During the past 2 years, CN has been an advisor or consultant to Biohaven, Clexio Biosciences Ltd., Johnson and Johnson, Novartis, and Otsuka, has received royalties from UpToDate, and research support from National Institute of Mental Health. RM, ER, DT, AT, RR, CJ, RK, MK, MKL, MAB, EB, and DB reported no biomedical financial interests or potential competing interests. SL serves on DSMBs for KeifeRX and the NIH IPAT study. She has received speaking honoraria from Eisai and IMPACT-AD and serves as a consultant for Vaccinex and the eSMARTER trial. She is on the JAMA Neurology editorial board and receives research funding and other support from NIH and the Alzheimer’s Association. AJS receives support from multiple NIH grants and has received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); NIH NHLBI (MESA Observational Study Monitoring Board); Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior). MWW has served on the Scientific Advisory Boards for Pfizer, BOLT International, Neurotrope Bioscience, Alzheon, Inc., Alzheimer’s Therapeutic Research Institute (ATRI), Eli Lilly, U. of Penn’s Neuroscience of Behavior Initiative, National Brain Research Centre (NBRC), India, Dolby Family Ventures, LP, and ADNI. PA has research grants from NIH, Lilly and Eisai, and consults with Merck, Roche, Genentech, Abbvie, Biogen, ImmunoBrain Checkpoint and Arrowhead. PSI consults with Roche and Merck.

Ethics approval and consent to participate

All participants provided written informed consent and all study procedures were approved by an Institutional Review Board.

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Mackin, R.S., Rhodes, E., Kassel, M. et al. Cortico-limbic volume abnormalities in late life depression are distinct from β amyloid and white matter pathologies. Mol Psychiatry 30, 1267–1276 (2025). https://doi.org/10.1038/s41380-024-02677-4

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