GWAS links APOE to neuropsychiatric symptoms in mild cognitive impairment and dementia

Abstract

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.

FIGURE 1

Regional p‐value plots for the six significant associations. Purple diamond indicates lead SNP for each association signal. Red points indicate SNPs passing the genome‐wide significant (GWS) threshold of 5 × 10⁻⁸, and blue points indicate other tested SNPs in the region. Blue line indicates recombination rate. (A) Region on chromosome 19 with GWS SNPs in five NPS domains. (B) Chromosome 9 region with GWS SNP in agitation. NPS, neuropsychiatric symptoms in dementia; SNP, single‐nucleotide polymorphism.

FIGURE 2

Proportion of APOE lead SNP effect mediated by age of onset or duration of cognitive impairment. The proportion mediated was estimated using R package mediation. Each bar corresponds to one of the five NPS with significant GWAS SNPs. Error bars indicate 95% confidence interval. (A) Proportion mediated by age of onset of cognitive impairment. (B) Proportion mediated by impairment duration. APOE, apolipoprotein E; NPS, neuropsychiatric symptoms in dementia; SNP, single‐nucleotide polymorphism.

FIGURE 3

Proportion of APOE lead SNP effect mediated by cognitive impairment severity. The proportion mediated was estimated using R package mediation. Each bar corresponds to one of the five NPS with significant GWAS SNPs. Error bars indicate 95% confidence interval. (A) Proportion mediated by cognitive impairment severity represented by binary MCI/dementia diagnosis. (B) Proportion mediated by cognitive impairment severity represented by global CDR score. APOE, apolipoprotein E; GWAS, genome‐wide association studies; MCI, mild cognitive impairment; NPS, neuropsychiatric symptoms in dementia; SNP, single‐nucleotide polymorphism.

FIGURE 4

Odds ratio estimates for lead SNPs in discovery and replication cohorts. Odds ratio estimates are from the NACC discovery analysis (filled circles) or BioVU or ADNI replication analyses (filled squares). The NPS outcomes in the discovery analysis and ADNI analysis were defined using NPI or NPI‐Q responses. The any NPS outcome in the BioVU analysis was defined using receipt of antipsychotic and/or antidepressant medication within 1 year before or any time after a patient's first MCI or dementia ICD code. Asterisks for replication results indicate effects that are significant at alpha = 0.05 after Bonferroni correction for the number of independent tests performed in each analysis (two tests in BioVU, six tests in ADNI). ADNI, Alzheimer's Disease Neuroimaging Initiative; ICD, International Classification of Diseases; MCI, mild cognitive impairment; NACC, National Alzheimer's Coordinating Center; NPI, Neuropsychiatric Symptom Inventory; NPI‐Q, Neuropsychiatric Symptom Inventory Questionnaire; NPS, neuropsychiatric symptoms in dementia; SNP, single‐nucleotide polymorphism.