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[Preprint]. 2024 Jan 30:2024.01.30.24301966.
doi: 10.1101/2024.01.30.24301966.

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

Terry E Goldberg  1   2 , D P Devanand  1   3 , Zhiqian Fang  1   4 , Hyun Kim  1 , Elizabeth Rueppel  1 , Aren Tucker  1 , Scott Carlson  1 , Seonjoo Lee  1   4
Affiliations

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

Terry E Goldberg et al. medRxiv. .

Update in

Abstract

Background: Our goal in this study was 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 cognition or neurobehaviors.

Methods: A total of 1199 cases with available neurobehavioral, cognition and neuropathological data were included. We then 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, but not extent of diffuse amyloid plaques, 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 in keeping with known features of the disease.

Conclusions: We found strong evidence for partial mediation of NPI symptoms by cognition, suggesting that cognitive limitations that may have influenced understanding (or misunderstanding) the environment with impacts on 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 as an outcome, suggesting that medial temporal regions that support memory may be sensitive to non-amyloidogenic and non-tau related pathophysiological processes.

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

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Figures

Figure 1:
Figure 1:
Mediation analyses testing the causal pathways depicted in the schematic figure. In these pathways, e4 (when present) always served as the independent predictor (exposure) and NPI items (when present) always served as the outcome. Histopathology served either as a mediator, or when e4 was controlled, as an exposure. Cognition served either as an outcome (if histopathology was present) or a mediator when NPI items were the outcome. This set of analyses respects the neurobiologic plausibility and logic that e4 is causative for ADRD pathologies (AD, LBD, CAA), which then may cause or otherwise mediate cognitive changes and/or NPI changes.
Figure 2:
Figure 2:
Mediation 1: E4 -> AD/LBD/CAA (ADRD pathologies) -> Memory test delay The figure shows the respective magnitude of the indirect and direct path when APOE e4 served as the exposure, ADRD pathologies (AD, LB, and CAA (called AMY) the multiple mediators, and Logical Memory as the outcome. The thickness of the bars is proportional to the relative effect: AD pathology had the largest mediated effect on Logical Memory. Note also E4 had a significant direct effect. *=p<.5, **=p<.01, +=p<.05 FDR corrected
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Figure 3A: Mediation 2: AD (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3B: Mediation 2: LBD (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3C: Mediation 2 CAA (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3D: Mediation 3: E4 -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for ADRD Figure 3E: Mediation 4: E4 -> AD(ADRD pathology) ->NPI (control for Memory test delay and adjusted for other ADRD pathologies) Figure 3F: Mediation 4: E4 -> LBD (ADRD pathology) -> NPI (control for Memory test delay and adjusted for other ADRD pathologies) Figure 3G: Mediation 4: E4 -> CAA (ADRD pathology) -> NPI (control for memory test and adjusted for other ADRD pathologies) Mediations in which Logical Memory Delayed served as a mediator or outcome. Figures 3A 3B and 3C show the strength and significance level (FDR adjusted) of mediated and direct effects from the three ADRD neuropathologies to NPI items with memory as the mediator. 3A=AD, 3B=LBD, and 3C=CAA. Height of the bars represent the magnitude of the effect. Figure 3D shows the strength and significance of the direct effect from e4 (as the exposure) to each NPI items and the strength of the indirect paths in which memory served as the mediator. Figures 3E, 3F, and 3G show the strength and significance of the indirect effect between e4 (the exposure) and each items when the ADRD neuropathologies served as mediators (3E AD, 3F LBD, and 3F CAA) and the respective direct effects from e4 to NPI items.
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Figure 3A: Mediation 2: AD (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3B: Mediation 2: LBD (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3C: Mediation 2 CAA (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3D: Mediation 3: E4 -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for ADRD Figure 3E: Mediation 4: E4 -> AD(ADRD pathology) ->NPI (control for Memory test delay and adjusted for other ADRD pathologies) Figure 3F: Mediation 4: E4 -> LBD (ADRD pathology) -> NPI (control for Memory test delay and adjusted for other ADRD pathologies) Figure 3G: Mediation 4: E4 -> CAA (ADRD pathology) -> NPI (control for memory test and adjusted for other ADRD pathologies) Mediations in which Logical Memory Delayed served as a mediator or outcome. Figures 3A 3B and 3C show the strength and significance level (FDR adjusted) of mediated and direct effects from the three ADRD neuropathologies to NPI items with memory as the mediator. 3A=AD, 3B=LBD, and 3C=CAA. Height of the bars represent the magnitude of the effect. Figure 3D shows the strength and significance of the direct effect from e4 (as the exposure) to each NPI items and the strength of the indirect paths in which memory served as the mediator. Figures 3E, 3F, and 3G show the strength and significance of the indirect effect between e4 (the exposure) and each items when the ADRD neuropathologies served as mediators (3E AD, 3F LBD, and 3F CAA) and the respective direct effects from e4 to NPI items.
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Figure 3A: Mediation 2: AD (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3B: Mediation 2: LBD (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3C: Mediation 2 CAA (ADRD pathology) -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for E4 (control other ADRD) Figure 3D: Mediation 3: E4 -> Memory test (delay) -> Psychiatric (NPI endorsement, last) controlled for ADRD Figure 3E: Mediation 4: E4 -> AD(ADRD pathology) ->NPI (control for Memory test delay and adjusted for other ADRD pathologies) Figure 3F: Mediation 4: E4 -> LBD (ADRD pathology) -> NPI (control for Memory test delay and adjusted for other ADRD pathologies) Figure 3G: Mediation 4: E4 -> CAA (ADRD pathology) -> NPI (control for memory test and adjusted for other ADRD pathologies) Mediations in which Logical Memory Delayed served as a mediator or outcome. Figures 3A 3B and 3C show the strength and significance level (FDR adjusted) of mediated and direct effects from the three ADRD neuropathologies to NPI items with memory as the mediator. 3A=AD, 3B=LBD, and 3C=CAA. Height of the bars represent the magnitude of the effect. Figure 3D shows the strength and significance of the direct effect from e4 (as the exposure) to each NPI items and the strength of the indirect paths in which memory served as the mediator. Figures 3E, 3F, and 3G show the strength and significance of the indirect effect between e4 (the exposure) and each items when the ADRD neuropathologies served as mediators (3E AD, 3F LBD, and 3F CAA) and the respective direct effects from e4 to NPI items.
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