Open Access Research

Genetic association between APOE*4 and neuropsychiatric symptoms in patients with probable Alzheimer's disease is dependent on the psychosis phenotype

Drew Christie1, Jane Shofer1, Steven P Millard1, Ellen Li6, Mary Ann DeMichele-Sweet3, Elise A Weamer4, M Ilyas Kamboh5, Oscar L Lopez4, Robert A Sweet346 and Debby Tsuang27*

Author Affiliations

1 VISN-20 Mental Illness, Seattle, WA, USA

2 Geriatric Research, Education and Clinical Centers, Seattle, WA, USA

3 Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA

4 Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

5 Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

6 VISN-4 Mental Illness, Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA

7 Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA

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Behavioral and Brain Functions 2012, 8:62  doi:10.1186/1744-9081-8-62

Published: 27 December 2012



Neuropsychiatric symptoms such as psychosis are prevalent in patients with probable Alzheimer’s disease (AD) and are associated with increased morbidity and mortality. Because these disabling symptoms are generally not well tolerated by caregivers, patients with these symptoms tend to be institutionalized earlier than patients without them. The identification of protective and risk factors for neuropsychiatric symptoms in AD would facilitate the development of more specific treatments for these symptoms and thereby decrease morbidity and mortality in AD. The E4 allele of the apolipoprotein E (APOE) gene is a well-documented risk factor for the development of AD. However, genetic association studies of the APOE 4 allele and BPS in AD have produced conflicting findings.


This study investigates the association between APOE and neuropsychiatric symptoms in a large sample of clinically well-characterized subjects with probable AD (n=790) who were systematically evaluated using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Behavioral Rating Scale for Dementia (BRSD).


Our study found that hallucinations were significantly more likely to occur in subjects with no APOΕ4 alleles than in subjects with two Ε4 alleles (15% of subjects and 5% of subjects, respectively; p=.0066), whereas there was no association between the occurrence of delusions, aberrant motor behavior, or agitation and the number of Ε4 alleles. However, 94% of the subjects with hallucinations also had delusions (D+H).


These findings suggest that in AD the Ε4 allele is differentially associated with D+H but not delusions alone. This is consistent with the hypothesis that distinct psychotic subphenotypes may be associated with the APOE allele.

Alzheimer’s disease; Apolipoprotein E; Genetics; Behavior; Hallucinations