Effects of Apolipoprotein E4 Genotype on Cerebro-cerebellar Connectivity, Brain Atrophy, and Cognition in Patients with Alzheimer's Disease

Introduction: While several studies have substantially revealed the influence of the apolipoprotein E4 genotype (APOE4) on the vulnerability of Alzheimer's disease (AD), there are still far fewer studies investigating whether and how APOE4, in the absence of the amyloid-β (Aβ), alters regional brain atrophy, cerebro-cerebellar connectivity and cognitive performance in AD patients.

Methods: We employed MRI and neuropsychological data from 234 old adults with AD dementia, including 143 APOE4-positive (with ε2/ε4, ε3/ε4, or ε4/ε4 alleles) and 91 APOE4-negative (with ε2/ε2, ε2/ε3 or ε3/ε3), to investigate the cerebro-cerebellar connectivity in three cerebro-cerebellar brain networks: default mode network, motor network and affective-limbic network. Amyloid PET images were used to evaluate individual Aβ burdens, later used as covariates. Regional volumetric and cortical thickness measures were quantified in both the cerebellum and the cerebrum using the cerebellum segmentation algorithm and Freesurfer5.3, respectively.

Results: Our corrected functional connectivity (FC) results showed that APOE4 carriers (APOE4+) had lower FC within the cerebro-cerebellar motor network. In addition, significant group differences in regional cortical thickness were observed in the left Crus I, the right VIIB, left superior frontal, and right middle temporal gyri. Group differences in regional brain volumes were observed in the left lobule V and right parstriangularis. Furthermore, multiple linear regression analysis indicated that APOE4+ AD patients show greater episodic memory impairment.

Conclusion: Since amyloid-β, age, education, and gender were included as confounds in the statistical models, our findings suggest that APOE4 independently contributes to brain atrophy, disrupted FC, and associated memory declines in AD patients.