To assess functional connectivity in posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) and evaluate how within and between-network functional connectivity differs based on the apolipoprotein E (APOE) ε4 status.  

APOE ε4 influences atrophy and tau deposition in patients with atypical Alzheimer’s disease (AD), with APOE ε4 carriers having greater predisposition to medial temporal involvement. This raises questions on whether the APOE genotype would influence memory network connectivity, a network mainly comprised of medial temporal structures.  

One-hundred forty amyloid-positive PCA (n=58) and LPA (n=82) patients were recruited by the Neurodegenerative Research Group and underwent structural and resting state functional MRI. Spatially preprocessed data were analyzed to explore the default mode network (DMN), salience, language, visual and memory networks, using a region of interest approach in Conn toolbox. Bayesian hierarchical linear models (BHLM) adjusted for age and sex, assessed the influence of APOE ε4 on within and between-network connectivity.

We found reduced within-network connectivity in the memory and language networks in LPA, with an increase in salience network connectivity in PCA, in APOE ε4 carriers compared to non-carriers. APOE ε4 did not influence memory within-network connectivity in PCA. Between-network analysis showed evidence of reduced connectivity from the DMN in both groups, with reduced DMN-to-salience and DMN-to-language network connectivity in PCA APOE ε4 carriers, and reduced DMN-to-visual network connectivity in LPA APOE ε4 carriers. In addition, we found reduced connectivity from the visual-to-language and visual-to-salience networks in APOE ε4 carriers compared to non-carriers in both PCA and LPA. Both network-level and voxel-level findings concurred with the BHLM findings, specifically showing reductions in the within-network connectivity for the memory network in LPA APOE ε4 carriers.

The APOE genotype influences brain connectivity, both within and between-networks, in atypical AD variants. However, there was evidence that the modulatory effects of APOE differ across phenotype.