Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting memory and cognition in elderly. Both genetic and environmental factors have been involved in the pathogenesis of AD. Apolipoprotein E (APOE) gene is accepted worldwide as a genetic factor for sporadic AD. However, the APOE gene only accounts for about 65% of all sporadic AD cases, indicating that other genes are involved in the etiology of sporadic AD (Richard and Amoyuel 2001).

Recent studies have shown evidence that cholesterol metabolism has an important role in the pathogenesis of AD. High serum cholesterol concentration increases the risk of AD (Notkola et al. 1998; Kivipelto et al. 2001).

Brain cholesterol is synthesized locally and is independent from nutritional intake (Jurevics and Morell 1995). Excess brain cholesterol derives either from increased synthesis or is due to neuronal cell death and needs to be eliminated from the brain (Goodrum 1991). Furthermore, it has been demonstrated that cholesterol affects the pathogenic mechanisms of the disease by modulating the amyloid precursor protein processing; high serum cholesterol is a factor that increases Aß biogenesis and Aß toxicity (Borroni et al. 2004).

Brain cholesterol is very stable compared to the cholesterol of the periphery, and it is mainly synthesized locally, as its transfer is restricted by the blood–brain barrier (Ma et al. 2006).

The turnover of cholesterol in the brain occurs via conversion of excess cholesterol into 24S-hydroxcholesterol, which is then secreted from the central nervous system into the plasma across the blood–brain barrier (Tedde et al. 2006).

24S-Hydroxycholesterol is the major cholesterol elimination product of the brain. More than 90% of plasma 24S-hydroxycholesterol originates from the brain; however, the exact transport mechanism for the elimination of 24S-hydroxycholesterol from brain into blood is unknown (Björkhem et al. 1998). Compared to controls, serum 24S-hydroxycholesterol/cholesterol ratios had decreased and were lower during the progress of AD. High levels of neurotoxic 24S-hydroxycholesterol, especially during early stages of AD, might have lead to advanced neurodegeneration, and thus, 24S-hydroxycholesterol is suggested to be an additional risk factor (Kölsch et al. 2002).

In addition, it is believed that the cerebrospinal fluid (CSF) concentration of 24S-hydroxycholesterol is altered in AD-related neurodegeneration, and thus, CSF 24S hydroxcholesterol may be a marker for monitoring the onset and progression of the disease (Papassotiropoulos et al. 2002).

The Cyp46 enzyme is a member of the cytocrome P-450 family proteins and converts cholesterol to 24S-hydroxycholesterol. Cyp46 is expressed exclusively in the brain, where it regulates the elimination of excess cholesterol by adding a hydroxyl group to cholesterol producing a product that is more soluble than cholesterol and able to be exported from the brain (Bjorkhem et al. 1998; Lund et al. 1999; Tedde et al. 2006).

Interestingly, polymorphisms in the CYP46 gene (which encodes for cholesterol 24S-hydroxylase) influence both Aß peptide load in the brain and the genetic risk for late-onset sporadic AD (LOAD) (Kolsch et al. 2003; Wolozin 2003). It is suggested that increases in the membrane distribution of cholesterol (in contrast to total cholesterol content) may provide an enriched environment for Aß production and release in the brain (Gibson et al. 2003; Kolsch et al. 2003). In addition, Aß peptide induction of membrane-associated oxidative stress may contribute to altered ceramide and cholesterol metabolism that in turn trigger AD-type neurodegeneration and brain disease (Cutler et al. 2004)

A single nucleotide polymorphism (T/C) (rs754203) in intron 2 of CYP46 gene has been identified and reported to be significantly associated with increased risk for LOAD. According to the report, the frequency of CYP46 T allele and TT genotype was significantly higher in AD patients from Switzerland, Greece, and Italy than in controls (Papassotiropoulos et al. 2003). In contrast, Borroni et al. (2004) reported that CYP46C allele might act as a risk factor for LOAD in Italian patients, meaning that the susceptibility polymorphism might differ in different ethnic groups (Wang et al. 2004).

Recently, Kölsch et al. (2009) identified two single nucleotide polymorphisms (SNPs) in CYP46A1 influenced AD risk and suggest that CYP46A1 gene variations might act as risk factors for AD via influence on brain cholesterol metabolism.

This was a key initiative, considering the importance of studies about this issue. The aim of this paper is to report the results of studies about AD genetics and the CYP46 gene that have been published in the last 9 years.

Case–Controls Studies

The first publication about the relationship between CYP46 and AD was published by Bogdanovic et al. (2001). Since this publication, a lot of research has been done to elucidate the importance of the CYP46 gene in the pathogenesis of AD.

The studies that analyzed the association of CYP46 in development of LOAD, between 2001 and 2009 years, are summarized in Table 1.

Table 1 A summarized analysis of the association between AD and CYP46
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With respect to the alleles (T/C) in the region rs754203 that be considered risk factors for LOAD, it is observed that 60% from the studies revealed the allele C association (Table 2)

Table 2 A summarized description of the risk for AD related to CYP46 C/T polymorphism in case–control studies
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In view of the contradictory results previously reported about the connection between CYP46 polymorphisms and AD, it is possible that the reasons for these controversial results would be caused by ethnical variability in different populations, methodological differences, or both. To confirm a connection between CYP46 as well as genetic control of cholesterol homeostasis in general and the pathogenesis of AD, further research is needed, including analysis of other genes influencing CNS cholesterol and amyloid metabolism and/or neighboring CYP46.