Effects of APOE ε4 and Neuropathological Diagnoses on Neuropsychiatric Symptoms: Mediation Analyses and Likely Causation in an Integrated National Alzheimer's Coordinating Center Database

Biol Psychiatry Cogn Neurosci Neuroimaging. 2024 Jul;9(7):650-659. doi: 10.1016/j.bpsc.2024.01.012. Epub 2024 Feb 8.


Background: In this study, we sought to identify paths from APOE ε4 to neurobehaviors itemized on a neuropsychiatric inventory (Neuropsychiatric Inventory-Questionnaire [NPI-Q]) that involved neuropathologies associated with APOE ε4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status) as well as direct paths from APOE ε4 to neurobehaviors.

Methods: A total of 1199 cases with available neurobehavioral, cognition, and neuropathological data were included. We conducted a series of causal mediation analyses in which APOE ε4 always served as the independent variable, and NPI-Q neurobehavioral items, when included in the mediation analysis, served as the outcome. Neuropathologies or cognition served as mediators.

Results: Multiple significant indirect paths from APOE ε4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage drove the findings. A significant direct effect of APOE ε4 on memory was also identified. Additionally, Lewy body disease, when treated as an exposure, had a direct effect on hallucinations consistent with features of the disease.

Conclusions: We found strong evidence for partial mediation of NPI-Q symptoms by cognition, suggesting that cognitive limitations may have promoted maladaptive behavior. In addition, neuritic amyloid plaque levels and Braak stage, but not diffuse amyloid plaque extent, were key in NPI-Q-mediated associations, suggesting the possibility that synaptic failure plays an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Finally, we found strong evidence that APOE ε4 may have direct effects on cognition when we used verbal episodic memory but not global cognitive status as an outcome.

Keywords: APOE; Alzheimer’s disease; Amyloid; Lewy body disease; Neurobehavior; Tau.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / pathology
  • Alzheimer Disease* / physiopathology
  • Apolipoprotein E4* / genetics
  • Brain / pathology
  • Databases, Factual
  • Female
  • Humans
  • Male
  • Mediation Analysis
  • Neuropsychological Tests


  • Apolipoprotein E4