Lack of association of the cholesterol 24-hydroxylase (CYP46) intron 2 polymorphism with Alzheimer's disease.
An association was recently reported between an increased risk of Alzheimer's disease and an intron 2 AA genotype of CYP46, the enzyme hydroxylating cholesterol to 24S-hydroxycholesterol. Moreover, CYP46 AA-carriers were found to have increased levels of amyloid-beta and tau in brain and cerebrospinal fluid. We determined the CYP46 intron 2 genotype in a cohort of 178 AD and 105 non-demented control subjects, but found no significant association with AD for any of the individual genotypes or alleles. Further, in an autopsy confirmed subset of this cohort, the proposed CYP46 risk genotype was not associated with any increase in the brain levels of amyloid-beta40, amyloid-beta42 or in the levels of amyloid plaques and neurofibrillary tangles. Despite growing evidence implicating cholesterol metabolism in AD risk and Abeta generation, our data does not support a robust genetic relationship between the CYP46 intron 2 polymorphism and AD risk or neuropathology.
Ingelsson
Martin
M
Harvard Medical School, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Jesneck
Jennifer
J
Irizarry
Michael C
MC
Hyman
Bradley T
BT
Rebeck
G William
GW
D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D000072556:Cholesterol 24-Hydroxylase; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007438:Introns / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013250:Steroid Hydroxylases / Q000235:genetics*
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase