Sex Modifies the Associations of APOEɛ4 with Neuropsychiatric Symptom Burden in Both At-Risk and Clinical Cohorts of Alzheimer’s Disease

Article type: Research Article

Authors: Dissanayake, Andrew S.^{a; 1} | Tan, Yu Bin^{a; 1} | Bowie, Christopher R.^{b; c} | Butters, Meryl A.^d | Flint, Alastair J.^{e; f} | Gallagher, Damien^{f; g; i} | Golas, Angela C.^{b; f} | Herrmann, Nathan^{f; g} | Ismail, Zahinoorⁿ | Kennedy, James L.^{b; f} | Kumar, Sanjeev^{b; f} | Lanctot, Krista L.^{f; g; i} | Mah, Linda^{f; j} | Mulsant, Benoit H.^{b; f} | Pollock, Bruce G.^{f; k; l} | Rajji, Tarek K.^{b; f; l} | Tau, Michael^{a; f; h} | Maraj, Anika^{f; h} | Churchill, Nathan W.^{a; h} | Tsuang, Debby^m | Schweizer, Tom A.^{a; h} | Munoz, David G.^{a; h} | Fischer, Corinne E.^{a; f; h; *} | for the PACt-MD Study Group

Affiliations: [a] Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON, Canada | [b] Centre for Addiction and Mental Health, Toronto, ON, Canada | [c] Queen’s University, Kingston, ON, Canada | [d] University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA | [e] Centre for Mental Health, University Health Network, Toronto, ON, Canada | [f] Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada | [g] Sunnybrook Health Sciences Centre, Toronto, ON, Canada | [h] Unity Health, St. Michaels Hospital, University of Toronto, Toronto, Ontario, Canada | [i] Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada | [j] Rotman Research Institute, Baycrest Health Science Centre, Toronto, ON, Canada | [k] Campbell Family Mental Health Research Institute, Division of Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, ON, Canada | [l] Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada | [m] GRECC, VA Puget Sound and Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA | [n] Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

Correspondence: [*] Correspondence to: Dr. Corinne Fischer, Room 17-044, CC Wing, St. Michael’s Hospital, 30 Bond St, Toronto, Ontario, M5B 1W8, Canada. Tel.: +1 416 864 5320; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Recent work suggests that APOE ɛ4/4 females with Alzheimer’s disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS). Objective:To examine the interaction of sex and APOE ɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261). Methods:Regression models examined the interactive effects of sex and APOE ɛ4 on the number of NPS experienced and NPS Severity. APOE ɛ3/4 and APOE ɛ4/4 were pooled in the at-risk cohort due to the sample size. Results:In the at-risk cohort, there was a significant sex*APOE ɛ4 interaction (p = 0.007) such that the association of APOE ɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOE ɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOE ɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOE ɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males. Conclusion:Our study suggests that sex modifies the association of APOE ɛ4 on NPS burden. APOE ɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.

Keywords: Alzheimer’s disease, APOE4, behavioral and psychological symptoms of dementia, biomarkers, gender differences, major depressive disorder, mild cognitive impairment, neuropsychiatry, Neuropsychiatric Inventory Questionnaire, psychosis

DOI: 10.3233/JAD-220586

Journal: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1571-1588, 2022