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-Abeta (Abeta) production in hiPSC-derived cortical neurons, but suppressed hiPSC-derived microglial-mediated Abeta clearance, leading to Abeta accumulation. Neither Olanzapine nor Risperidone had any significant effect on hiPSC-derived microglial synaptosome phagocytosis. Conversely, Clozapine significantly reduced Abeta production in neurons, and increased microglial uptake of Abeta 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 Abeta and synapses in a drug specific manner. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Dementia Research Institute UK Van Geest Trust Swedish Research Council (grant No. 2019-01088) Alzheimers Research UK (RE18385) Karolinska Institutet (Senior Researcher Award and Strategic Research Area in Epidemiology) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Regional Ethical Review Board in Stockholm, Sweden, gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.