Effects of APOE e4 and Neuropathological Diagnoses on Neuropsychiatric Symptoms: Mediation Analyses and Likely Causation in an Integrated NACC Database

Background: We sought to identify paths from APOE e4 to neurobehaviors itemized on a neuropsychiatric inventory that involved neuropathologies associated with e4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status), as well as direct paths from e4 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 R in which e4 always served as the independent variable and Neuropsychiatric Inventory (NPI) neurobehavioral items, when included in the mediation, the outcome. Neuropathologies or cognition served as mediators.

Results: Multiple significant indirect paths from e4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage drove the findings. A significant direct effect of e4 to 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 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 mediated associations suggesting the possibility that synaptic failure play an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Last, we found strong evidence that e4 may have direct effects on cognition when we used verbal episodic memory but not global cognitive status, as an outcome.