Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease

Neurodegener Dis. 2005;2(5):233-41. doi: 10.1159/000090362.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Aged
  • Alleles
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Brain / pathology
  • Cholesterol / blood
  • Chromosomes, Human, Pair 10 / genetics*
  • Female
  • Gene Expression Regulation, Enzymologic
  • Genetic Markers
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / pathology
  • Polymorphism, Single Nucleotide
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk
  • Steroid Hydroxylases / genetics*

Substances

  • 5' Untranslated Regions
  • Amyloid beta-Peptides
  • Genetic Markers
  • RNA, Messenger
  • lathosterol
  • Cholesterol
  • Steroid Hydroxylases
  • cholesterol 25-hydroxylase