Review
Genetic evidence for the involvement of lipid metabolism in Alzheimer's disease

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Abstract

Alzheimer's disease (AD) is the most common cause of dementia in the elderly and presents a great burden to sufferers and to society. The genetics of rare Mendelian forms of AD have been central to our understanding of AD pathogenesis for the past twenty years and now the genetics of the common form of the disease in the elderly is beginning to be unravelled by genome-wide association studies. Four new genes for common AD have been revealed in the past year, CLU, CR1, PICALM and BIN1. Their possible involvement in lipid metabolism and how that relates to AD is discussed here.

Introduction

Alzheimer's disease (AD) is a common and devastating neurodegeneration that creates enormous social, emotional and financial burdens for sufferers, their carers and for health services. It is responsible for the majority of dementia in the elderly [1]. AD is generally a disease of old age, although there are rare early onset forms that may account for up to 1% of the total burden [2]. The major risk factors for AD susceptibility are age and family history. The prevalence of AD in western populations is around 1% at age 65 rising to 25–35% of those over 85 and without new treatments the numbers of people with AD in late life will rise as life expectancy rises [3]. AD has long been recognised to be heritable and recent estimates of heritability range from 58 to 79% [4]. The known heritability of AD has underpinned many years of genetic studies to uncover the genes that underlie the various forms of this inexorably progressive disease.

Section snippets

The genetics of AD

Why is looking for genes that contribute to the causes of AD important? Genetic analysis of the association of DNA variants with disease does not require any prior biological knowledge of the disease. So genetics can reveal the aetiology of a disease without other biological information and this is its major strength.

A variety of strategies have been used to identify genes which influence AD. In family based linkage studies family members with and without the disease are compared and it is

Genetics and lipid metabolism in AD

Epidemiological studies have shown that lipid metabolism is likely to be involved in risk for AD. There is evidence that high cholesterol levels in mid-life are correlated with later dementia, and statins, which lower cholesterol levels, may have a protective effect against the development of dementia [51]. It is therefore important in understanding the aetiology of AD that the new genetic findings should be examined in the context of their potential effects on lipid metabolism.

Conclusions and future perspectives

The power of GWAS lies in their ability to reveal genes that underlie susceptibility to disease without knowledge of the underlying biology. GWAS have been hugely productive but have as yet only detected variations in DNA that can account for a small proportion of heritability of these complex diseases [35]. Meta-analyses of multiple studies can increase the power of these studies as demonstrated in Type II diabetes where a meta-analysis of three large studies increased the numbers of

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