Cholesterol and Alzheimers Disease: Clinical and Experimental Models Suggest Interactions of Different Genetic, Dietary and Environmental Risk Factors

Kumar      Sambamurti; Ann-Charlotte      Granholm; Mark   S.   Kindy; Narayan   R.   Bhat; Nigel   H.   Greig; Debomoy   K.   Lahiri; Jacobo   E.   Mintzer

Abstract

Alzheimers disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (Aβ) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1 / 2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as secretases participate in APP processing leading to the generation of either Aβ or non-amyloid proteins. However, the mechanisms of neurotoxicity of Aβ and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the ε4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Aβ has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors.

Keywords: aging, cognition, diets, dementia, high fats, apolipoprotein e, secretase, myelin, memory