DOI: 10.1002/alz.080622 ISSN: 1552-5260

APOE ε4 and cognitive networks: Centrality of episodic memory nodes in patients with mild cognitive impairment

Matteo De Marco, Laura M Wright, Jose Manuel Valera‐Bermejo, Cameron E Ferguson
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



The literature based on univariate models does not lead to unequivocal conclusions on the effects of APOE variability on cognition. We thus hypothesised that the impact of APOE‐ε4 on cognitive functioning can be reliably captured by graph‐theory.


Cognitive datasets were extracted from the National Alzheimer’s Coordinating Center’s database. After the application of stringent exclusion criteria, 16,173 participants with a known APOE ε3ε3/ε4ε3/ε4ε4 genotype were retained: 8,118 controls, 3,482 MCI patients and 4,573 AD‐dementia patients. ε3ε3 individuals were classified as “non‐carriers”, while ε4ε3/ε4ε4 individuals were tagged as “carriers”. Two independent sub‐cohorts were defined based on the version of the battery used to characterise cognitive profiles. Pairwise Markov random‐field models of cognitive functioning were constructed in “R” using the “qgraph” package, following published methodological guidelines. Nine cognitive nodes were established, and partial correlations were run to calculate the statistical strength of all node‐to‐node edges. This was regularised via the LASSO penalty‐imposing method, to control graph sparsity. Differences in global and nodal metrics between ε4 carriers and non‐carriers were tested via permutation‐based Network Invariance Tests. These analyses were run separately in each sub‐cohort and within each diagnostic status. “Expected Influence” was analysed as the centrality metric of interest, to assess how influential each node is within its network.


A significant APOE‐dependant effect emerged from the analysis of the Logical‐Memory nodes in MCI patients in both sub‐cohorts. While non‐carriers showed equal centrality in immediate and delayed recall, the latter was significantly less central among carriers. These findings were replicated in the sub‐groups of sole amnestic‐MCI patients (n = 2,971), were independent of differences in network communities, clinical severity or other demographic factors. No effects were found in the other diagnostic groups or in global network metrics.


APOE‐ε4 influences nodal properties of cognitive networks when patients are clinically classified as MCI. Our findings expand this area of knowledge by characterising the statistical effect of the ε4 allele in terms of its differential impact on immediate and delayed recall, and how this results in specific network effects. The study of the wider cognitive network can complement univariate approaches in characterising the effects of risk factors.

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