| Objective The progressive neurodegenerative disease Alzheimer's disease(AD)characterized by progressive memory impairment,accompanied by other cognitive declines,abnormal mental behavior and personality changes.The distinct pathological changes,including senile plaques formed by the accumulation of amyloid ?-protein(A?)and tangles formed by aggregates of hyperphosphorylated tau,are thought to occur decades before clinical symptoms emerge in AD.Mild cognitive impairment(MCI)is an intermediate state between healthy aging and AD,associated with an increased risk of dementia.Individuals with MCI show cognitive decline greater than expected for their age and education level,but this decline does not interfere with everyday activities.Academia agrees that AD-derived MCI is the prodromal stage of AD and a better therapeutic time window for AD clinical trials.Apolipoprotein E(Apo E)?4 has been identified as the strongest known genetic risk factor for AD.However,the effect of Apo E ?4 on clinical and biological heterogeneity of AD remains unclear,particularly at the prodromal stage.Here,we evaluate the association of Apo E ?4 with cerebrospinal fluid(CSF)biomarkers,clinical cognitive performance and neuroimaging regions in MCI participants based on the AT(N)system,which is increasingly important to develop a precise assessment of AD.Methods 197 A+T+MCI individuals(prodromal AD)from the Alzheimer's Disease Neuroimaging Initiative(ADNI)cohort stratified into Apo E ?4(+)and Apo E ?4(-)according to Apo E genotype.18F-Florbetapir mean standardized uptake values ratios(SUVR)>1.1 as the threshold for A?-positivity(A+)and CSF biomarkers p-tau levels>23 pg/m L as the threshold for fibrillar tau-positivity(T+).Multivariate analysis of variance was performed to compare the differences of cerebrospinal fluid markers,cognitive scores and brain atrophy(measured by structural MRI)between the ApoE ?4(-)group and the ApoE ?4(+)group.Also,we performed a linear regression model to assess the correlation between signature ROIs of structural MRI and cognitive scores in the prodromal AD participants.Results 1.ApoE ?4(+)prodromal AD participants had a slightly lower age at onset,lower levels of CSF A?1-42,higher levels of t-tau,compared to Apo E ?4(-)prodromal AD subjects.2.ApoE ?4(+)prodromal AD participants had worse memory,executive function and global cognition,smaller subcortical volume of the bilateral hippocampus,along with thinner cortical thickness in the right entorhinal,adjusted for age,gender,and year of education.3.Compared to female without ApoE ?4,female ApoE ?4 carriers had lower A?1-42 levels and higher t-tau levels,more severe cognitive impairment and brain atrophy.But there were no significant differences among male patients.4.After knowing the ApoE ?4 status,specific MRI regions can be correlated to the cognitive domain.Conclusion In prodromal AD participants,ApoE ?4 status has an important effect on clinical cognitive domains,and may be regulated by gender.After ascertaining the ApoE ?4 status,specific MRI regions can be correlated to the cognitive domain and will be helpful for precise assessment in prodromal AD. |
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