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

CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain. To study the association of polymorphic sites on CYP46 with Alzheimer disease (AD) traits and with the risk of the development of AD. 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. Specialized centers for memory disorders in Switzerland, Greece, and Italy. 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. 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). 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.