The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

Background: Apolipoprotein E (APOE) epsilon 4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of APOE epsilon 4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of APOE epsilon 4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer's Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-beta (A beta). Methods: Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF A beta 42 and tau detection, APOE epsilon 4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer's disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of APOE epsilon 4 and CSF tau levels and cognitive scores in persons with and without A beta deposition (A beta+ and A beta-). Results: The prevalence of APOE epsilon 4 is higher in EMCI and LMCI than in CN (p < 0.001 for both), and in LMCI than in EMCI (p = 0.001). APOE epsilon 4 allele was significantly higher in A beta+ subjects than in A beta- subjects (p < 0.001). Subjects who had a lower CSF A beta 42 level and were APOE epsilon 4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. Conclusions: An APOE epsilon 4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by A beta. We conclude that APOE epsilon 4 may be an important mediator of tau pathology and cognition in the early stages of AD.