Effects of APOE ε2 allele on basal forebrain functional connectivity in mild cognitive impairment

BackgroundBasal forebrain cholinergic system (BFCS) dysfunction is associated with cognitive decline in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Apolipoprotein E (APOE) epsilon 2 is a protective genetic factor in AD and MCI, and cholinergic sprouting depends on APOE. ObjectiveWe investigated the effect of the APOE epsilon 2 allele on BFCS functional connectivity (FC) in cognitively normal (CN) subjects and MCI patients. MethodWe included 60 MCI patients with APOE epsilon 3/epsilon 3, 18 MCI patients with APOE epsilon 2/epsilon 3, 73 CN subjects with APOE epsilon 3/epsilon 3, and 36 CN subjects with APOE epsilon 2/epsilon 3 genotypes who had resting-state functional magnetic resonance imaging data from the Alzheimer's disease Neuroimaging Initiative. We used BFCS subregions (Ch1-3 and Ch4) as seeds and calculated the FC with other brain areas. Using a mixed-effect analysis, we explored the interaction effects of APOE epsilon 2 allele x cognitive status on BFCS-FC. Furthermore, we examined the relationships between imaging metrics, cognitive abilities, and AD pathology markers, controlling for sex, age, and education as covariates. ResultsAn interaction effect on functional connectivity was found between the right Ch4 (RCh4) and left insula (p < 0.05, corrected), and between the RCh4 and left Rolandic operculum (p < 0.05, corrected). Among all subjects and APOE epsilon 2 carriers, RCh4-left Insula FC was associated with early tau deposition. Furthermore, no correlation was found between imaging metrics and amyloid burden. Among all subjects and APOE epsilon 2 carriers, FC metrics were associated with cognitive performance. ConclusionThe APOE epsilon 2 genotype may play a protective role during BFCS degeneration in MCI.

Automated summary

This study investigated the effect of the APOE epsilon 2 allele on basal forebrain cholinergic system functional connectivity in cognitively normal and mild cognitive impairment patients. The results showed an interaction effect between APOE epsilon 2 genotype and functional connectivity, and the functional connectivity was associated with cognitive performance. Therefore, the APOE epsilon 2 genotype may have a protective role in mild cognitive impairment.