International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Mann KM, Lamb BT

Department of Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, United States

The APOE e 4 allele is the most significant genetic risk factor associated with Alzheimer’s disease to date.  Epidemiological studies have demonstrated that inheritance of one or more e 4 alleles affects both the age of onset and severity of pathology development.  Dosage of APOE e 2 and e 3 alleles, however, appear to be protective against the effects of e 4.  Although much of the biology of APOE in peripheral cholesterol metabolism is understood, its role in brain cholesterol metabolism and its impact on AD development is less defined.  Several studies have shown that cholesterol may be an independent risk factor for AD and can directly affect the production of Ab, the constituent of senile plaques.  We have characterized APOE knock-in (KI) mice, which express each human allele under endogenous regulatory elements, on a defined C57BL6/J background.  These mice have significantly different serum cholesterol levels and steady-state brain APOE levels, yet have equivalent brain cholesterol levels. However, the presence of human APOE significantly increases brain Ab levels in a genomic-based model of AD, irrespective of allele.  These data indicate an independent role for APOE in cholesterol metabolism in the periphery relative to the CNS. Additionally, altered levels of cholesterol and APOE are insufficient to influence Ab metabolism in a mouse model of Alzheimer’s disease. Future experiments will address the impact of aging and diet with regards to APOE genotype and amyloid deposition.

[an error occurred while processing this directive]