Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism.

Background: CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain.

Objective: To study the association of polymorphic sites on CYP46 with Alzheimer disease (AD) traits and with the risk of the development of AD.

Design: Alzheimer disease traits (beta-amyloid load, beta-amyloid peptides, hyperphosphorylated tau protein) were assessed in brain tissues and in the cerebrospinal fluid of patients with AD and control subjects. Genetic associations were studied in 2 independent populations.

Setting: Specialized centers for memory disorders in Switzerland, Greece, and Italy.

Participants: Fifty-five brain tissues from nondemented elderly patients for the histopathological studies; 38 patients with AD and 25 control subjects for the cerebrospinal fluid studies; 201 patients with AD and 248 control subjects for the genetic association studies.

Results: A polymorphism of CYP46 was associated with increased beta-amyloid load in brain tissues as well as with increased cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau protein. Moreover, this CYP46 polymorphism was associated with higher risk of late-onset sporadic AD in 2 independent populations (odds ratio, 2.16; 95% confidence interval [CI], 1.41-3.32; P<.001). The additional presence of 1 or 2 apolipoprotein E epsilon4 alleles synergistically increased the risk of AD to an odds ratio of 9.6 (95% CI, 4.9-18.9; P<.001) as compared with 4.4 for apolipoprotein E epsilon4 alone (95% CI, 2.8-6.8; P<.001).

Conclusion: CYP46 influences brain beta-amyloid load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD.