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[Preprint]. 2025 Feb 2:2025.01.31.25321498.
doi: 10.1101/2025.01.31.25321498.

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

Selina M Vattathil  1 , Freida Blostein  2   3 , Tyne W Miller-Fleming  2 , Lea K Davis  2 ; Alzheimer’s Disease Genetics Consortium (ADGC), Alzheimer’s Disease Neuroimaging Initiative; Thomas S Wingo  1   4 , Aliza P Wingo  5   6
Affiliations

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

Selina M Vattathil et al. medRxiv. .

Update in

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 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.

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Conflict of interest statement

9 Declaration of Interests None.

Figures

Figure 1.
Figure 1.. Regional P-value plots.
Purple diamond indicates lead SNP in locus. Red points indicate SNPs passing the genome-wide significant (GWS) threshold of 5 × 10−8, and blue points indicate SNPs with p-values below the GWS threshold. A. Region on chromosome 19 with GWS SNPs n five NPS domains. B. Chromosome 9 region with GWS SNP in agitation.
Figure 2.
Figure 2.. Proportion of APOE lead SNP effect mediated by age of onset of cognitive decline.
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.
Figure 3.
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.
Figure 4:
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 one 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).
See this image and copyright information in PMC

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