Introduction: Neuropsychiatric symptoms in dementia (NPS) collectively refer to behavioral and psychological symptoms affecting individuals with mild cognitive impairment (MCI) or Alzheimer's disease or related dementia (ADRD). NPS are among the most troubling aspects of living with dementia and their treatments have limited efficacy. We aim to investigate genetic variants contributing to NPS to identify new therapeutic targets.

Methods: We performed a genome-wide association study (GWAS) for nine NPS domains measured by the NPI-Q in 12,800 participants of European ancestry with MCI or ADRD recruited by Alzheimer's disease research centers across the U.S.

Results: We found genome-wide significant signals for agitation, anxiety, apathy, delusions, and hallucinations in the APOE locus that were driven by the APOE ε4 allele. We replicated these findings in two independent datasets. Mediation analyses revealed that MCI/ADRD severity only partially mediated the GWAS signals, except for apathy.

Discussion: These findings suggest the APOE ε4 allele influences NPS independently of and beyond its effect on ADRD.