Inverse effect of the APOE epsilon4 allele in late- and early-onset Alzheimer’s disease

Abstract

In Alzheimer's disease patients (AD), the age at onset (AAO) ranges from 40 to 90. Usually, AD patients who develop symptoms before the age of 65 are classified as early onset (EO). The best known genetic risk factor for AD is the ε4 allele of the apolipoprotein E (APOE). In this study, 474 subjects with AD were consecutively recruited in the memory clinic of the Santa Lucia Foundation in Rome. The best fitting model for the discrimination between EO and late onset (LO) was chosen based on lowest value of the Bayesian Information Criterion, which suggests the theoretical model with minimal deviation from the empirical distribution function of AAO in our sample. The FMM was used to compare EO and LO groups with respect to the following demographic and clinical variables: gender, age, education, MMSE and NPI. Furthermore a quantitative assessment of ADL and IADL was performed. Finally, the frequency of the APOE ε4 allele was compared in EO and LO groups. Using the admixture analysis, we established that the AAO discriminating EO from LO-AD was 63-64. Higher education was associated with earlier onset in the EO but not in LO, and duration of illness was associated with earlier onset only in LO. The ε4 allele was associated with later onset in EO but earlier onset in LO. Finally, increased impairment in ADL, IADL and NPI was associated with later onset only in the LO subgroup. Thus, the ε4 allele of the APOE gene was significantly associated with both EO and LO distributions but with opposite effect, suggesting genetic heterogeneity. Additional studies are needed to further clarify the genetic mechanisms differentiating EO- and LO-AD.

Definition of Late Onset Alzheimer’s Disease and Anticipation Effect of Genome-Wide Significant Risk Variants: Pilot Study of the APOE e4 Allele

“…We observed that APOE e4 anticipates onset only in a homogeneous group of LOAD, while on the other hand the same allele did not show anticipation in EOAD [2]. However, the relationship between the e4 allele and AAO across different homogenous groups has not yet been replicated using appropriate statistics.…”

“…Usually, AD patients who develop symptoms before the age of 65 are considered early-onset AD (EOAD) [1]; however, the majority of patients develops AD symptoms after 65, namely late-onset AD (LOAD). In our previous publication [2], we observed that the AAO in AD is not normal and can be better explained as a mixture of two normal distributions comprising EOAD and LOAD (Fig. 1a).…”

“…All Italian and Brazilian samples were already genotyped for the APOE e4 allele since they are included in previously published AD genetic studies [2,10]. The analytical pipeline of this study is divided into three different stages: (1) mixture analysis to determine the optimal number of AAO subgroups; (2) FMM analysis to test the anticipation effect of the APOE e4 in LOAD; (3) meta-analysis of all three samples to determine the pooled anticipatory effect of the e4 allele.…”

“…This sample-specific analysis was performed because we showed that the ideal cut-off for separating LOAD can be better determined using the mixture analysis [2] rather than using an arbitrary cut-off. To confirm the heterogeneity of the onset, we compared the 3 samples using the 2-sample Kolmogorov-Smirnov test (Fig.…”

The Correlation between Genotype and Phenotype of Alzheimer's Disease

“…Studies of LOAD suggest that the duration of illness tends to be longer in people who have a positive family history or in carriers of the APOE4 allele. However, it has since been shown that this relationship no longer holds true once the confounding effects of AAO have been taken into account [117]. Thus, in LOAD, increased survival is more directly related to an earlier AAO, which is influenced by a number of factors that are not exclusively genetic.…”