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Clinical Manifestations.

Gayathiri Rajkumar1, Marc A Khoury2, Mila Valcic2

  • 1Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michaels Hospital, Toronto, ON, Canada.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

APOE4 homozygosity increases psychosis risk in males and females with Alzheimer's disease, particularly hallucinations. These findings highlight sex-specific effects of the APOE4 allele on psychosis symptoms.

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Area of Science:

  • Neuroscience
  • Genetics

Background:

  • The apolipoprotein E4 (APOE4) allele is a known genetic risk factor for Alzheimer's disease (AD).
  • Previous research indicated that homozygous APOE4 status, particularly in females with Lewy Body (LB) pathology, is associated with increased psychosis risk.

Purpose of the Study:

  • To investigate the impact of APOE4 carrier status (homozygous, heterozygous, non-carrier) and sex on the risk of visual hallucinations, auditory hallucinations, and delusions in Alzheimer's disease patients.
  • To determine if female-specific effects are more pronounced for visual hallucinations, potentially as a marker for LB pathology.

Main Methods:

  • Data was extracted from the NACC database, limited to patients with an Alzheimer's disease diagnosis.
  • Psychosis symptoms (hallucinations and delusions) were assessed using Neuropsychiatric Inventory subscores.
  • Binary logistic regression analyses were performed separately for males and females, controlling for age, education, MoCA, and MMSE scores.

Main Results:

  • Overall, APOE4 homozygotes showed a higher likelihood of auditory hallucinations and delusions compared to heterozygotes and non-carriers, respectively.
  • Female APOE4 homozygotes had a greater likelihood of hallucinations compared to non-carriers.
  • Male APOE4 homozygotes exhibited increased overall and visual/auditory hallucinations compared to heterozygotes, but not non-carriers.

Conclusions:

  • APOE4 homozygosity elevates psychosis risk in males (vs. heterozygotes) and females (vs. non-carriers), primarily affecting hallucinations.
  • Pooled analyses indicated APOE4's influence on delusions and auditory hallucinations across sexes.
  • Sex-specific effects of APOE4 may be more significant for hallucinations than delusions, warranting further investigation in larger cohorts.