Olanzapine, Risperidone and Clozapine prescribing is associated with increased risk for Alzheimers Disease reflecting antipsychotic-specific effects on microglial phagocytosis

Epidemiological data provides evidence for a positive correlation between schizophrenia diagnosis and an increased risk to develop dementia. Whether and how use of antipsychotic medication may contribute to this association is however unknown. We therefore conducted a pharmaco-epidemiological study based on Swedish Patient and Prescribed Drug Registers to investigate the effect of three antipsychotics, Olanzapine, Risperidone, and Clozapine, on dementia risk. Our data suggest that prescription of all three antipsychotics is significantly associated with increased risk of Alzheimers disease (AD) and other dementias including vascular dementia. To provide a nexus of causality to this association, we explored the impact of these drugs on microglia and neurons using cells derived from human induced pluripotent stem cells (hiPSCs). Acute exposure to Olanzapine and Risperidone did not significantly alter amyloid-{beta} (A{beta}) production in hiPSC-derived cortical neurons, but suppressed hiPSC-derived microglial-mediated A{beta} clearance, leading to A{beta} accumulation. Neither Olanzapine nor Risperidone had any significant effect on hiPSC-derived microglial synaptosome phagocytosis. Conversely, Clozapine significantly reduced A{beta} production in neurons, and increased microglial uptake of A{beta} but also synaptosomes, consistent with higher lysosomal levels in Clozapine-exposed hiPSC-derived microglia. These data provide the first evidence that antipsychotics prescribed to individuals with schizophrenia are associated with increased risk for dementia and suggest potential cellular bases for this effect via the modulation of microglia uptake of A{beta} and synapses in a drug specific manner.