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
- Desai P, Dekosky ST, Kamboh MI. 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.
- Kölsch H, Lütjohann D, Ludwig M, Schulte A, Ptok U, Jessen F, von Bergmann K, Rao ML, Maier W, Heun R. Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease. Mol Psychiatry. 2002;7(8):899-902. PubMed.
- Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, Russell DW, Björkhem I. 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.
- Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S, Thal D, Nicosia F, Iakovidou V, Maddalena A, Lütjohann D, Ghebremedhin E, Hegi T, Pasch T, Träxler M, Brühl A, Benussi L, Binetti G, Braak H, Nitsch RM, Hock C. 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.
- Wolozin B. Cyp46 (24S-cholesterol hydroxylase): a genetic risk factor for Alzheimer disease. Arch Neurol. 2003 Jan;60(1):16-8. PubMed.