The Effect of the APOE-e4 Allele on the Cholinergic Circuitry for Subjects With Different Levels of Cognitive Impairment

Background: Cholinergic deficiency has been suggested to associate with the abnormal accumulation of A beta and tau for patients with Alzheimer's disease (AD). However, no studies have investigated the effect of APOE-epsilon 4 and group differences in modulating the cholinergic basal forebrain-amygdala network for subjects with different levels of cognitive impairment. We evaluated the effect of APOE-epsilon 4 on the cholinergic structural association and the neurocognitive performance for subjects with different levels of cognitive impairment. Methods: We used the structural brain magnetic resonance imaging scans from the Alzheimer's Disease Neuroimaging Initiative dataset. The study included cognitively normal (CN, n = 167) subjects and subjects with significant memory concern (SMC, n = 96), early mild cognitive impairment (EMCI, n = 146), late cognitive impairment (LMCI, n = 138), and AD (n = 121). Subjects were further categorized according to the APOE-epsilon 4 allele carrier status. The main effects of APOE-epsilon 4 and group difference on the brain volumetric measurements were assessed. Regression analyses were conducted to evaluate the associations among cholinergic structural changes, APOE-epsilon 4 status, and cognitive performance. Results: We found that APOE-epsilon 4 carriers in the disease group showed higher brain atrophy than non-carriers in the cholinergic pathway, while there is no difference between carriers and non-carriers in the CN group. APOE-epsilon 4 allele carriers in the disease groups also exhibited a stronger cholinergic structural correlation than non-carriers did, while there is no difference between the carriers and non-carriers in the CN subjects. Disease subjects exhibited a stronger structural correlation in the cholinergic pathway than CN subjects did. Moreover, APOE-epsilon 4 allele carriers in the disease group exhibited a stronger correlation between the volumetric changes and cognitive performance than non-carriers did, while there is no difference between carriers and non-carriers in CN subjects. Disease subjects exhibited a stronger correlation between the volumetric changes and cognitive performance than CN subjects did. Conclusion: Our results confirmed the effect of APOE-epsilon 4 on and group differences in the associations with the cholinergic structural changes that may reflect impaired brain function underlying neurocognitive degeneration in AD.

Automated summary

The study revealed significant differences in the associations between APOE-epsilon 4 and cholinergic structural changes among subjects with different levels of cognitive impairment, reflecting impaired brain function underlying neurocognitive degeneration in AD.