Apolipoprotein E-ε4 allele predicts escalation of psychotic symptoms in late adulthood
Introduction
A large body of research has focused on the predictors of illness chronicity in schizophrenia (Ram et al., 1992). Most studies have found that early age of onset, male sex, poor premorbid adjustment, duration of untreated psychosis, negative symptoms, and persistence of symptoms following first episode all forecast poor prognosis (Austin et al., 2013; Haro et al., 2011; Harrison et al., 2001). However, apart from neurodevelopmental processes that are presumably reflected in age of onset, these predictors provide limited insight into mechanisms of illness, as they are difficult to distinguish from the core deficits of the diagnosis itself. Consequently, research is increasingly focused on identifying biomarkers of disease risk and progression. Identification of such objective markers would provide clinicians with a tool to predict prognosis and plan treatment accordingly.
Two years after the initial publication showing that APOE-ε4 is a critical risk factor for Alzheimer's disease (Strittmatter et al., 1993), Harrington et al. (1995) presented evidence that it was also associated with schizophrenia (OR = 2.7; 95% CI = [1.8–4.0], p < 0.0001). A subsequent meta-analysis of 17 case-control studies published between 1995 and 2004 supported the increased prevalence of schizophrenia in ε4 carriers but observed significant heterogeneity among studies, and concluded that the effect may not be robust (Xu et al., 2006). The most recent meta-analysis of 28 case-control studies conducted between 1995 and 2011 detected no association (González-Castro et al., 2015).
Conclusion of no relationship between APOE-ε4 and schizophrenia is premature for two reasons. First, APOE-ε4's effects are known to be moderated by age, as demonstrated by its association with Alzheimer's disease. Given the variation in the ages of the samples reported in case-control studies of schizophrenia, it is important to test whether age moderates the association between APOE-ε4 and diagnosis before dismissing it.
Second, it is possible that APOE-ε4 affects the manifestation or progression of specific symptoms of schizophrenia. Schizophrenia is a heterogeneous disorder, with core symptoms including hallucinations and delusions, disorganization, and negative symptoms of avolition and inexpressivity (American Psychiatric Association, 2013; Blanchard and Cohen, 2006; Kring et al., 2013; Strauss et al., 2013; Strauss et al., 2012). The presence and severity of these symptoms vary between individuals, and within individuals over time. A handful of cross-sectional studies have examined whether APOE-ε4 is associated with specific symptoms or diagnostic subtypes. Two groups reported associations between APOE-ε4 and negative symptoms (Martorell et al., 2001; Pickar et al., 1997). Another group identified a link with positive symptoms (Al-Asmary et al., 2015). More commonly, findings linking APOE-ε4 and diagnostic subtypes have been null (Akanji et al., 2009; Arnold et al., 1997; Durany et al., 2000; Jönsson et al., 1996; Kecmanović et al., 2010), although this literature is likely limited by the poor reliability of diagnostic subtypes (Tandon et al., 2013). However, no prior study has examined whether APOE-ε4 is associated with symptom trajectories as participants age.
The present study investigated the role of age in the relationship of APOE-ε4 with schizophrenia by first examining its associations with trajectories of symptoms (hallucinations/delusions, disorganization, avolition, and inexpressivity) during the 20 years following first hospitalization. We hypothesize that, given the link between APOE-ε4 and progressive dementias, the effect of APOE-ε4 will emerge with increasing age. In addition, we extended prior meta-analyses by conducting a meta-regression of 29 case-control studies to test whether age explains the heterogeneity of effects among previous studies of APOE-ε4 and schizophrenia.
Section snippets
Design & Sample
Data were drawn from the Suffolk County Mental Health Project, a longitudinal first-admission study of psychosis. Participants were recruited from the 12 inpatient facilities of Suffolk County, New York. The Stony Brook University Committee on Research Involving Human Subjects and the review boards of participating hospitals approved the protocol annually. To be eligible for study inclusion, participants with psychosis had to reside in Suffolk County, be between ages 15–60, speak English, and
APOE genotype and symptom trajectories
Table 3 reports the associations between APOE-ε4 and symptom domains at baseline, as well as symptom trajectories from 6 months to 20 years. APOE-ε4 was not associated with any of the symptom scores at baseline, controlling for age, prescription of an antipsychotic,1 and the first ten principal components of genetic covariance. Consistent with this, the trajectory analyses found that the APOE
Discussion
This study sought to determine whether APOE-ε4, a genetic variant long known to influence risk of a number of chronic diseases including cardiovascular disease and dementia (Eichner et al., 2002; Poirier et al., 1993), shapes the course of psychosis. First, we examined contributions of this polymorphism to the course of schizophrenia tracked over 20 years, and found that participants with APOE-ε4 experienced a progressive increase in reality distortion (hallucinations and delusions) after age
Funding body agreements and policies
This work was supported by the National Institutes of Health (MH44801 to EB, MH094398 to RK, MH085548 to Carlos Pato, subcontract to EB, and MH085542 to Carlos Pato, subcontract to EB, and MH117646 to TL); and by the Brain and Behavior Research Foundation (NARSAD Young Investigator Grant to RK).
Conflicts of interest
The authors (KJ, SC, KL, LF, TL, AM, DC, GP, EB, & RK) have no conflicts of interest to disclose.
Acknowledgements
The authors gratefully acknowledge the support of the participants and mental health community of Suffolk County for contributing their time and energy to this project. They are also indebted to the study coordinators for their dedicated efforts, the interviewers for their careful assessments, and the psychiatrists who derived the consensus diagnoses.
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