Loss of Apolipoprotein E Receptor LR11 in Alzheimer Disease

Abstract

Alzheimer disease (AD) is the most important cause of aging-related dementia, and its prevalence has risen dramatically with increases in the oldest segments of the population. While the mechanisms underlying the disease remain poorly understood, deposition of senile plaques composed of fibrillar aggregates of amyloid-β (Aβ) peptide is believed to play an important pathogenic role.^1,2 Converging lines of evidence also implicate apolipoprotein E (ApoE), low-density lipoprotein (LDL) receptors, and lipid metabolism in AD pathogenesis. Epidemiologic data link serum cholesterol level, dietary fatty acids, and exposure to certain lipid-lowering drugs to AD risk.^3-5 Apolipoprotein E is the most abundant apolipoprotein expressed in brain, and a common polymorphism in the APOE gene represents the major genetic risk factor for sporadic, late-onset cases of AD.⁶ Other genetic association studies implicate members of the LDL receptor family, which bind ApoE, in AD pathogenesis.^7,8 The mechanism underlying these associations is unclear. Apolipoprotein E binds Aβ peptide⁹ and may modulate Aβ fibrillization and amyloid deposition, or promote internalization of Aβ through the LDL receptor–related protein (see reviews^10,11).