A cluster of cholesterol-related genes confers susceptibility for Alzheimer's disease

J Clin Psychiatry. 2005 Jul;66(7):940-7.

Abstract

Objective: Polygenic diseases are related to the complex interplay of genetic variations. We evaluated whether clusters of cholesterol- and lipid-related genetic variations are associated with Alzheimer's disease.

Method: We analyzed 12 cholesterol-related single nucleotide polymorphisms and 48 control polymorphisms in 545 study participants (Alzheimer's disease group N = 284; control group N = 261). Diagnoses of Alzheimer's disease were made according to the NINCDS-ADRDA criteria. Multi-locus genetic association analysis was done with the set-association method. Dates of data collection were from January 2000 to December 2003.

Results: We identified a cluster of polymorphisms in APOE, SOAT1, APOE 5'-untranslated region, OLR1, CYP46A1, LPL, LIPA, and APOA4 conferring significant (p = .0002) susceptibility for Alzheimer's disease. This gene cluster reached a diagnostic accuracy of 74% and correlated significantly (p = .018) with the levels of the brain cholesterol catabolite 24S-hydroxycholesterol in the cerebrospinal fluid.

Conclusion: Our results establish a novel approach for the identification of disease-related genetic clusters and demonstrate the need for multi-locus methods in the genetics of complex diseases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / genetics*
  • Apolipoprotein A-V
  • Apolipoproteins / genetics
  • Apolipoproteins A
  • Apolipoproteins E / genetics
  • Brain / metabolism
  • Brain Chemistry / genetics
  • Cholesterol / genetics*
  • Cholesterol 24-Hydroxylase
  • Cross-Cultural Comparison
  • Female
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing / methods
  • Greece / ethnology
  • Humans
  • Hydroxycholesterols / cerebrospinal fluid
  • Hydroxycholesterols / metabolism
  • Male
  • Multigene Family / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, LDL / genetics
  • Receptors, Oxidized LDL
  • Risk Factors
  • Scavenger Receptors, Class E
  • Steroid Hydroxylases / genetics
  • Switzerland / ethnology
  • White People / genetics

Substances

  • APOA5 protein, human
  • Apolipoprotein A-V
  • Apolipoproteins
  • Apolipoproteins A
  • Apolipoproteins E
  • Hydroxycholesterols
  • OLR1 protein, human
  • Receptors, LDL
  • Receptors, Oxidized LDL
  • Scavenger Receptors, Class E
  • 24-hydroxycholesterol
  • Cholesterol
  • Steroid Hydroxylases
  • Cholesterol 24-Hydroxylase