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 but 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 Neuropsychiatric Symptom Inventory Questionnaire (NPI-Q) in 12,800 participants from Alzheimer's Disease Research Centers across the United States. We performed a replication analysis in two independent cohorts.
Results: We found genome-wide significant signals for agitation, anxiety, apathy, delusions, and hallucinations that were driven by the apolipoprotein E (APOE) ε4 allele. We replicated these findings in ADNI and BioVU cohorts. Mediation analyses revealed that, except for apathy, MCI/ADRD severity only partially mediated the GWAS signals.
Discussion: These findings suggest the APOE ε4 allele influences several NPS independently of and beyond its effect on ADRD.
Highlights: Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment and dementia. Effective NPS treatments are pressingly needed, and genetic studies can inform treatment targets to develop effective therapeutics. We conducted a genome-wide association study of NPS in over 12,800 individuals and a replication analysis in two independent cohorts. We found apolipoprotein E (APOE) single-nucleotide polymorphisms (SNPs) associated with multiple NPS domains beyond their effects on cognitive impairment.
Keywords: APOE; Alzheimer's disease; agitation; anxiety; apathy; cognitive impairment; delusions; dementia; genome‐wide association; hallucinations; neuropsychiatric symptoms in dementia.
© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
