The Impact of Amyloid Burden and APOE on Rates of Cognitive Impairment in Late Life Depression

Article type: Research Article

Authors: Rhodes, Emma^a | Insel, Philip S.^{b; c} | Butters, Meryl A.^d | Morin, Ruth^a | Bickford, David^b | Tosun, Duygu^{e; f} | Gessert, Devon^g | Rosen, Howie J.^h | Aisen, Paul^{g; i} | Raman, Rema^{g; i} | Landau, Susan^j | Saykin, Andrew^k | Toga, Arthur^l | Jack, Clifford R.^m | Weiner, Michael W.^{b; e; f} | Nelson, Craig^b | Mackin, Scott^{b; d; *} | on behalf of the Alzheimer’s Disease Neuroimaging Initiative¹ | the ADNI Depression Project²

Affiliations: [a] Mental Illness Research Education and Clinical Centers, Veterans Administration Medical Center, San Francisco, CA, USA | [b] Department of Psychiatry, University of California, San Francisco, CA, USA | [c] Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden | [d] Department of Psychiatry, Western Psychiatric Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [e] Veterans Administration Medical Center, San Francisco, CA, USA | [f] Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA | [g] University of Southern California, Los Angeles, CA, USA | [h] Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA | [i] Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego, CA, USA | [j] Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA | [k] Indiana University School of Medicine, Indianapolis, IN, USA | [l] Laboratory of Neuro Imaging, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA | [m] Department of Radiology, Mayo Clinic, Rochester, MN, USA

Correspondence: [*] Correspondence to: R. Scott Mackin, PhD, Department of Psychiatry, University of California, San Francisco, CA 94148, USA. Tel.: +1 415 476 7067; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Note: [2] Data used in preparation of this article were obtained from the ADNI Depression (ADNI-D) database (https://ida.loni.usc.edu/login.jsp?project=ADNID). As such, the investigators within the ADNI Depression Project contributed to the design and implementation of ADNI Depression and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI Depression investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective:To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods:Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results:LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls (H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I (p = 0.044), Logical Memory II (p = 0.011), and Trail Making Test –B (p = 0.032), and APOE ɛ4 genotype was associated with worse performance on Logical Memory I (p = 0.022); these relationships did not differ between LLD and ND. Conclusion:LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer’s disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.

Keywords: Amyloid, apolipoprotein E, cognitive impairment, late life depression

DOI: 10.3233/JAD-201089

Journal: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 991-1002, 2021