ApoE4 and Psychosis in Neurodegenerative and Non-Neurodegenerative Disease: A Scoping Review

Psychosis is a neuropsychiatric feature found across neurodegenerative conditions including Alzheimer’s disease (AD) and Parkinson’s disease (PD). It is also a common feature in psychiatric disorders such as schizophrenia. The apolipoprotein E epsilon 4 (ApoE4) allele is an established genetic risk factor for AD that may also increase the risk of psychosis. However, evidence regarding the association between ApoE4 and psychosis remains unclear. This paper evaluates the relationship between "ApoE" 4 carrier status and psychosis in both neurodegenerative (Alzheimer’s disease and Parkinson’s disease) and non-neurodegenerative disorders (schizophrenia). Additionally it explores whether sex and zygosity modulate this association.A literature review of studies identified through PubMed and Scopus was conducted. Thirty- one studies, were included that investigated the relationship between ApoE4 and psychosis in select neurodegenerative and psychiatric populations. Studies were included if they assessed ApoE4 status in relation to the presence, severity, or age of onset of psychosis.Among the 16 AD- focused studies, a positive association was reported in 11 while 4 showed no significant association and one showed an inverse correlation. ApoE4 carriers and ApoE4 homozygotes that were female were reported to have the strongest association. The three studies examining PD resulted in inconsistent findings limited by small sample sizes. With respect to schizophrenia, associations were predominantly null or inconsistent. There was limited evidence for the influence of sex or ApoE4 zygosity.Of note the risk was enhanced in female carriers and "ApoE" 4 homozygotes. In terms of PD results were conflicting, limited by small sample sizes. Schizophrenia studies produced findings that were predominantly null or equivocal, with no clear evidence that sex or zygosity influenced outcomes.ApoE4 positivity appears to have a stronger association with psychosis in AD compared to PD or schizophrenia. Available evidence suggests that this relationship may be modified by sex and ApoE4 zygosity and that female ApoE4 homozygotes are particularly vulnerable. Findings were however limited by substantial heterogeneity across studies and limited evidence in PD and schizophrenia populations. Thus larger studies are needed to clarify the role of ApoE4 in psychosis, particularly in non-AD cohorts.