APOE genotype and cholesterol levels in Lewy body dementia and Alzheimer disease: Investigating genotype-phenotype effect on disease risk

Background. APOE is the most recognized genetic risk factor for sporadic late-onset Alzheimer disease (AD). The role of APOE genotype in Lewy body dementia (LBD) is still unknown as well as the relationship between APOE genotype and cholesterol levels. Objective: The objective of this study was to explore the association between APOE genotype and cholesterol levels in patients with LBD and those with AD. Methods: Eighty-two patients with LBD were consecutively enrolled as well as a comparable number of patients with AD and comparison group. Each subject underwent a clinical and neuropsychologic evaluation and APOE genotyping, Results: The distribution of APOE genotypes signficantly differed between AD and LBD cases compared with the comparison group, with the APOE epsilon 4+ (epsilon 4+/epsilon 4+ or epsilon 4+/epsilon 4) genotype more frequent inpatient subgroups. Different models have been fitted, and total APOE epsilon 4-hypercholesterolemia complete interaction effect was claimed in predicting their relationship on disease outcome. Subjects with hypercholesterolemia and heterozygous for APOE epsilon 4 allele had more than threefold risk to develop AD compared both with the comparison group and with those with LBD. The risk to develop AD in hypercholesterolemic and APOE epsilon 4 homozygous subjects was 13-fold compared with the comparison group and those with LBD. Conversely, there was not evidence for APOE epsilon 4-hypercholesterolemia complete interaction effect in LBD and in the comparison group. Conclusions: This study highlighted that APOE is a risk factor not only for AD, but also for LBD, and that the APOE-cholesterol pathway differently affects AD and LBD. This approach may aid the search for the identification of an interactive effect of APOE genotype and modifiable risk factors, i.e., hypercholesterolemia, eventually resulting in individualized and effective cholesterol-lowering therapy in at-risk subjects.