Plasma Cholesterol and Risk for Late-onset Alzheimer's Disease

Angel Cedazo-Mínguez; Muhammad-Al-Mustafa Ismail; Laura Mateos

Disclosures

Expert Rev Neurother. 2011;11(4):495-498. 

In This Article

Abstract and Introduction

Abstract

Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disorder affecting millions of people worldwide. AD has a multifactorial origin, resulting from an interaction between genetic susceptibility and environmental risk factors. Genetic, epidemiological, experimental and clinical data strongly suggest that the metabolism of cholesterol has an important role in AD pathogenesis. Several studies have demonstrated that high concentrations of serum cholesterol increase the risk of AD. Statins, drugs that reduce cholesterol levels, have been investigated as a possible treatment for AD. However, the literature is not exempt of contradictory results. In this article, we review a recent article by Reitz et al. demonstrating that higher levels of high-density lipoprotein cholesterol, total cholesterol and non-high-density lipoprotein cholesterol are associated with lower risk of AD. In addition, we discuss the current state of knowledge regarding the relationship between plasma cholesterol and AD, stressing the need for understanding the molecular mechanisms behind this association.

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that constitutes the main cause of dementia in the elderly. Two well-established risk factors for AD are age and the presence of the ε4 isoform of apolipoprotein E (apoE). In the past decade, several risk factors have been associated with AD, including hypertension, diabetes mellitus, obesity, metabolic syndrome and hypercholesterolemia.[1] In addition, cholesterol metabolism has been previously implicated in AD pathogenesis.[2–4] However, epidemiological studies have reported contradictory results concerning the role of cholesterol as a risk factor for AD. Globally, a positive association with AD was found when cholesterol levels were measured in middle-aged individuals,[5] with the exception of the Honolulu Asia Study, where a cluster of cardiovascular factors increased the risk of vascular dementia (VaD) but not of AD.[6]

Epidemiological studies demonstrated that apoE4 carriers have a higher risk for both AD and an early onset of the disease.[7] Genetic studies have identified several cholesterol-related genes that are associated with AD.[8] It has been suggested that both genetic and environmental risk factors could act in synergy to confer the risk for AD.[9]

Based on evidence supporting hypercholesterolemia as a risk factor for AD, cholesterol synthesis inhibitors, such as statins, were proposed as valuable tools for therapeutic intervention. Despite the fact that the majority of retrospective studies with statins demonstrated a positive effect, others were not able to determine an association between the use of these drugs, cognitive decline and dementia or AD risk. It has been proposed that the different capacity of statins to pass the BBB, their different pleotropic effects, or the necessity to start treatment in very early phases of the disease may have caused these controversial results.[10–12]

Vascular dysfunction in the brain has long been recognized as a contributing factor to the development of VaD. More recently, accumulated evidence suggests that the development of AD may also be strongly related to underlying vascular problems.[13] Furthermore, it seems obvious to infer that a disturbance in plasma cholesterol levels or metabolism could participate in vascular dysfunctions, and therefore in the development of VaD.

The molecular mechanisms linking cholesterol with AD pathology are still unknown. Amyloidβ (Aβ) accumulation in the brain is thought to play a key role in the neurodegenerative processes and results from both brain overproduction and aberrant clearance of these peptides across the BBB.[14] In vitro studies have also demonstrated that intracellular cholesterol levels can modulate the processing of APP to Aβ and that the cleavage of APP by β- and γ-secretases occurs in cholesterol-rich microdomains within the neuronal membranes known as 'lipid rafts'. On the other hand, cholesterol metabolites were also demonstrated to modulate APP processing[15] and Aβ production.

Since the brain is separated from the plasma cholesterol by the BBB, it is intriguing how high serum cholesterol levels influence the prevalence of AD. Oxysterols are capable of passing through the BBB, and high levels of 27-hydroxycholesterol passing from the blood into the brain has been proposed as a possible mechanism.[16] Recent data demonstrated that high cholesterol and 27-hydroxycholesterol levels affect memory consolidation in experimental studies[17,18] and are intimately linked to the renin–angiotensin system overactivation observed in the brains of AD patients.[19]

Although midlife studies consistently associate high plasma cholesterol levels with dementia, this association is less clear in older people. Reitz et al. reported that high levels of high-density lipoprotein cholesterol (HDL-C) in elderly individuals are associated with a decreased risk of late-onset AD.[20] This result, which may seem controversial, has also been reported in other previous studies.[21]

In this article, we discuss possible explanations for these apparently controversial findings, and emphasize the need to understand how blood lipid levels participate in the pathogenetic mechanisms leading to different dementia-causing disorders.

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