In this week's issue of the Archives of Neurology, Andreas Papassotiropoulos and Roger Nitsch at the University of Zurich in Switzerland and collaborators from around Europe propose that a polymorphism in the gene for cholesterol 24-hydroxylase (CYP46) is a risk factor for late-onset Alzheimer's, and that the risk from this polymorphism is synergistic with the risk from the E4 allele of the gene for apolipoprotein E (ApoE).

The interest in CYP46 stems from evidence that regulation of brain cholesterol influences brain amyloid-beta (Aβ) levels (see ARF related news story and especially the extended comment by Ben Wolozin). Wolozin reviews much of this relationship in an editorial accompanying the current CYP46 report, including the role that CYP46 plays in converting cholesterol to 24-hydroxycholesterol, which can then exit cells. There have been prior investigations of a link between CYP46 and AD risk. Investigating the same CYP46 polymorphism as the current study (a T/C substitution termed rs754203, located in the intron between exons 2 and 3), researchers led by Ilyas Kamboh (see comment below) last August reported finding no link to AD risk (Desai et al., 2002). A second study by German scientists of a different, nearby polymorphism found a weak linkage signal Kolsch et al., 2002).

Papassotiropoulos and colleagues report results from three separate, if small, populations. Their histopathologic studies were done in brain tissue from 55 nondemented elderly subjects; CSF studies were performed on 38 patients with AD and 25 control subjects; and their genetic association data are from 201 AD patients and 248 control subjects.

The researchers found that the TT polymorphism was associated with increased Aβ, both in terms of brain amyloid load and CSF levels, as well as increased phosphorylated tau levels in CSF. The polymorphism was associated with a higher risk of late-onset AD (OR, 2.16; 95 percent CI, 1.41-3.32; P<.001). Moreover, the scientists also report a synergistic effect of the ApoE4 allele, where possession of the TT polymorphism along with either one or two E4 alleles increased the odds ratio to 9.6 (95 percent CI, 4.9-18.9; P<.001).

Because there are data suggesting that elevated cholesterol levels may increase amyloid production, the current results support the speculation that "functional alterations of cholesterol 24-hydroxylase may modulate cholesterol concentrations in vulnerable neurons, thereby leading to altered membrane composition and associated changes in amyloid precursor protein processing and Aβ production," write the authors.

Wolozin echoes this possibility in his editorial, but notes that one should not exclude the possibility that polymorphisms in CYP46 could have neurodegenerative effects that bypass Aβ. He adds that polymorphisms that increase CYP46 activity could produce higher levels of 24-hydroxycholesterol, which has been shown to be toxic to neurons. The current results appear to strengthen the possibility that reducing cholesterol levels in the brain could be a strategy for treating late-onset AD, however, other genetics labs must reproduce this linkage in additional patient samples.-Hakon Heimer.

References:
Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S, Thal D, Nicosia F, Iakovidou V, Maddalena A, Lutjohann D, Ghebremedhin E, Hegi T, Pasch T, Traxler M, Bruhl A, Benussi L, Binetti G, Braak H, Nitsch RM, Hock C. Increased brain b-amyloid load, phosphorylated tau, and risk of Alzheimer diseases associated with and intronic CYP46 polymorphism. Arch Neurol. 2003 Jan;60(1):29-35. Abstract

Wolozin B. Cyp46 (24S-cholesterol hydroxylase): A genetic risk factor for Alzheimer disease. Arch Neurol. 2003 Jan;60(1):16-8.Abstract

 

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  1. Papassotiropoulos et al. have described the association of an intronic polymorphism in the CYP46 gene with AD. They found this polymorphism to influence Aβ load, however, the authors failed to show an effect on cholesterol or 24S-hydroxycholesterol CSF levels, which may be important in this respect.

    This study is a continuation of the work Andreas Papassotiropoulos performed in our team in Bonn. In 1999, we showed that plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer's disease and vascular dementia (Lutjohann et al., 1999), and that this metabolite acts as a neurotoxin on SH-SY5Y cells (Kolsch et al., 1999). Later, we found that neurotoxicity of 24S-hydroxycholesterol leading to apoptosis is mediated by the generation of free radicals (Kolsch et al., 2001), and reported that plasma 24S-hydroxycholesterol is a peripheral indicator of neuronal degeneration (Papassotiropoulos et al., 2000). Our observation of increased 24S-hydroxycholesterol in cerebrospinal fluid in early stages of dementia was published recently (Papassotiropoulos et al., 2002). In a continuation of this work, we found that another polymorphism in the CYP46 gene (IVS3+43Cy´T) was associated with an increased CSF ratio of 24S-hydroxycholesterol/cholesterol in carriers of the C-allele, as well as with a higher risk of AD (Kolsch et al., 2002). Supporting the observation of Papassotiropoulos et al. that genetic variants of the CYP46 gene influence the Aβ levels as well as the risk of AD, we also observed increased Aβ levels in homocygote carriers of the C allele (Kölsch et al., unpublished). In contrast to the present paper of Papassotiropoulos et al., but in agreement with Desai et al., 2002, we could not find an association of the rs755814 polymorphism described by Papassotiropoulos et al. with AD. It may be mentioned that this polmorphism is currently denoted as a Gy´A polymorphism, but was recently named a Cy´T transition in reverse antisense sequence of the CYP46 gene.

    In contrast to Desai et al., both studies (Kolsch et al., 2002; Papassotiropoulos et al., 2003) support that Cyp46 polymorphism might influence the risk of AD by increasing β-amyloid levels. However, the relative relevance of the different polymorphisms in the CYP46 gene is not yet clear. It might even be speculated that a third, nearby polymorphism in linkage disequilibrium is the relevant actor. In contrast to the results of Papassotiropoulos, our study additionally indicates an important relevance of cholesterol metabolism, including the intracerebral metabolism of 24S-OH-cholesterol in AD. The relevance of cholesterol in AD is currently a major focus of theoretical and therapeutic studies.

    In summary, we strongly support Benjamin Wolozin's conclusions (see editorial accompanying Papassotiropoulos et al., 2003) that cholesterol metabolism is of major relevance in AD and that CYP46 polymorphisms seem to play an important role. The results concerning CYP46 should be proven by additional association, as well as functional, studies. Until these studies are performed, the present data should be discussed carefully.

  2. In our paper last year (Desai et al., 2002), we did not see any association of this intronic polymorphism with late-onset AD in our case-control cohort. One of the obvious differences between our study and this one is that our American White sample size was much larger (434 AD cases and 401 controls) than the one used in this study (201 AD cases and 248 controls). Since the question of power is a common concern in association studies, it is essential that such studies be performed on a large case-control sample having sufficient statistical power to avoid any false association. In our paper, we also examined the association of this polymorphism in a small sample of African Americans available in our center (61 cases and 54 controls). Although the distribution of this polymorphism was significantly different between white and blacks, no association was observed with AD in the black sample, either.

    Our data, based on a relatively large sample size, suggest that this intronic CYP46 polymorphism is not associated with the risk of AD. We cannot, however, rule out the possibility that other sequence variations in this gene may be associated with AD, but this awaits additional studies on relatively large case-control cohorts.

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References

News Citations

  1. Rotterdam Study Questions Links between Fat and Dementia Risk

Paper Citations

  1. . Genetic variation in the cholesterol 24-hydroxylase (CYP46) gene and the risk of Alzheimer's disease. Neurosci Lett. 2002 Aug 2;328(1):9-12. PubMed.
  2. . Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease. Mol Psychiatry. 2002;7(8):899-902. PubMed.
  3. . Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol. 2003 Jan;60(1):29-35. PubMed.
  4. . Cyp46 (24S-cholesterol hydroxylase): a genetic risk factor for Alzheimer disease. Arch Neurol. 2003 Jan;60(1):16-8. PubMed.

Further Reading

Papers

  1. . On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett. 2001 Nov 13;314(1-2):45-8. PubMed.
  2. . Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol. 2003 Jan;60(1):29-35. PubMed.
  3. . Cyp46 (24S-cholesterol hydroxylase): a genetic risk factor for Alzheimer disease. Arch Neurol. 2003 Jan;60(1):16-8. PubMed.

Primary Papers

  1. . Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol. 2003 Jan;60(1):29-35. PubMed.
  2. . Cyp46 (24S-cholesterol hydroxylase): a genetic risk factor for Alzheimer disease. Arch Neurol. 2003 Jan;60(1):16-8. PubMed.