Apolipoprotein E-ε4 allele predicts escalation of psychotic symptoms in late adulthood

Background: Research on a putative link between apolipoprotein-ε4 allele (APOE-ε4) and schizophrenia has been inconclusive. However, prior studies have not investigated the association between APOE-ε4 and symptom trajectories, nor has the existing literature taken into account the potentially moderating effect of age in genetic association studies. Methods: The association between APOE-ε4 and four symptom dimensions was investigated in a longitudinal study of 116 individuals with schizophrenia initially assessed during their first admission for psychosis and evaluated five times over the following 20 years. A meta-analysis identified 29 case-control studies of APOE-ε4 allele frequency in schizophrenia, which were analyzed using random-effects meta-regression to test the potentially moderating effect of age. Results: Longitudinal models identified a specific association between APOE-ε4 and symptom trajectories, showing that APOE-ε4 portends worsening severity of hallucinations and delusions in late adulthood among people with schizophrenia, at a rate of a 0.46 standard deviation increase per decade. Meta-analysis showed a significant effect of age: the association between APOE-ε4 and schizophrenia was not detectable in younger people but became pronounced with age, such that APOE-ε4 increased the odds of diagnosis by 10% per decade. Conclusions: Taken together, the meta-analysis and longitudinal analysis implicate APOE-ε4 as an age-related risk factor for worsening hallucinations and delusions, and suggest APOE-ε4 may play an age-mediated pathophysiological role in schizophrenia. The presence of an APOE-ε4 allele may also identify a subgroup of patients who require intensive monitoring and additional targeted interventions, especially in mid-to late-life.