Clinical Cohort Validation of Sex-Specific Effect of Apolipoprotein E Status on Psychosis in Alzheimer's Disease

Abstract

<h3>Introduction</h3> Psychosis is one of the most typical and persistent neuropsychiatric manifestations of AD where nearly half of AD patients experiences psychotic symptoms such as hallucinations and/or delusions (Ropacki & Jeste., 2005). Psychotic AD patients tend to have poorer overall health (Bassiony et al., 2000) and experience greater cognitive and functional impairments (Chui et al., 1994; Fischer et al., 2012). These qualities contribute to a reduced quality of life for patients and their caregivers. Researchers from our group found that psychosis risk in neuropathologically-diagnosed AD patients is significantly higher in females who are homozygous positive for <i>APOE</i> ε4 with the presence of Lewy body pathology (Kim et al., 2017). These results point to a sexual dimorphism in AD psychosis where the ε4 allele may play a larger role in influencing psychosis development in females. We hypothesize that AD patients with this high-risk profile (female and homozygous positive for <i>APOE</i> ε4) are more susceptible to psychosis, potentially leading to more severe symptoms as well as earlier disease onset respectively. As such, this exploratory study aims to validate the sex-specific effect of <i>APOE</i> ε4 status (i.e. high-risk profile) on psychosis in a clinical cohort. <h3>Methods</h3> We first obtained all required Research Ethics Board approval from St. Michael's Hospital and the National Alzheimer's Coordinating Centre (NACC). A series of parallel analyses were conducted via SPSS (Version 27.0.0.0). For each analysis, we first conducted a descriptive analysis of our sample including age, sex, cognitive status, psychosis status, and presence of the relevant alleles. Patients with CNS neoplasm, non-AD-induced dementia, and significant psychiatric co-morbidity were excluded as per the inclusion/exclusion criteria for NACC. Participants Selected participants from the NACC database had a presumptive etiological diagnosis of AD from a clinician. They also had available <i>APOE</i> ε4 status and Neuropsychiatric Inventory Questionnaire (NPI-Q) data. Subjects were categorized by high-risk profile. Subjects with either hallucinations or delusions as defined by the NPI-Q were considered psychotic (Figure 1). Procedure & Analyses We investigated the effect of having a high-risk profile (female and homozygous positive for <i>APOE</i> ε4) on age and neuropsychiatric test scores at initial visit, as well as presence and severity of psychotic symptoms (delusions or hallucinations). <h3>Results</h3> To investigate the effect of the high-risk profile on age, we conducted a one-way between-subjects analysis of variance in the high-risk vs. non-high-risk conditions. Subjects with the high-risk profile (M = 70.43, SD = 7.75) were significantly younger than those without the profile (M = 74.69, SD = 9.76) at the time of their initial visit [F(1, 16202) = 139.05, <i>p</i> < .001] (Figure 2). To investigate the effect of the high-risk profile on the presence of delusions and hallucinations, we conducted a binary logistical regression for each psychotic symptom. We found that the high-risk profile significantly predicted the presence of delusions, <i>b</i> = 0.302, df = 1, <i>p</i> = .004. There was no significance for hallucinations. Lastly, to study the effect of the high-risk profile on the severity of delusions and hallucinations, we conducted an ordinal logistical regression for each psychotic symptom. Subjects with the high-risk profile had a predicted increase of 0.388 in the log-odds of being in a more severe category for delusions, <i>p</i> = .041. Similarly, high-risk individuals had a predicted increase of 0.638 in the log-odds of being in a more severe category for hallucinations, <i>p</i> = .046. <h3>Conclusions</h3> From our results, the high-risk profile of being female and homozygous positive for <i>APOE</i> ε4 seems to be associated with an earlier age of initial visit, an increased presence of delusions and more severe psychotic symptoms. In terms of psychosis in AD, our findings are in line with our prior work suggesting <i>APOE</i> ε4 may play a modulatory role in the development of psychosis in female patients with AD, leading to earlier onset of symptoms, increased prevalence of delusions and more severe psychotic symptoms (Kim et al., 2017). Taken together, we believe that this high-risk profile may be a significant step towards understanding the mechanisms that underly AD and psychosis in AD. Future directions include elucidating the sex-specific cellular mechanisms on <i>APOE</i> ε4 status. <h3>Funding</h3> We wish to acknowledge the generosity of the St. Michael's Hospital Foundation and the Heather and Eric Donnelly endowment.