Papassotiropoulos Andreas, Streffer Johannes R, Tsolaki Magdalini, Schmid Simon, Thal Dietmar, Nicosia Francesca, Iakovidou Vassiliki, Maddalena Alessia, Lütjohann Dieter, Ghebremedhin Estifanos, Hegi Thomas, Pasch Thomas, Träxler Muriel, Brühl Annette, Benussi Luisa, Binetti Giuliano, Braak Heiko, Nitsch Roger M, Hock Christoph
Division of Pychiatry Research, University of Zurich, Switzerland.
Arch Neurol. 2003 Jan;60(1):29-35. doi: 10.1001/archneur.60.1.29.
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.
CYP46是编码胆固醇24 - 羟化酶的基因，在胆固醇的羟基化过程中起关键作用，从而介导其从脑内清除。
研究CYP46基因多态性位点与阿尔茨海默病（AD）特征以及AD发病风险的相关性。
在AD患者和对照者的脑组织及脑脊液中评估AD特征（β-淀粉样蛋白负荷、β-淀粉样肽、过度磷酸化tau蛋白）。在2个独立人群中研究基因相关性。
瑞士、希腊和意大利的记忆障碍专科中心。
55份来自非痴呆老年患者的脑组织用于组织病理学研究；38例AD患者和25名对照者用于脑脊液研究；201例AD患者和248名对照者用于基因相关性研究。
CYP46基因多态性与脑组织中β-淀粉样蛋白负荷增加以及脑脊液中β-淀粉样肽和磷酸化tau蛋白水平升高相关。此外，这种CYP46基因多态性与2个独立人群中晚发性散发性AD的较高风险相关（比值比，2.16；95%置信区间[CI]，1.41 - 3.32；P <.001）。与仅载脂蛋白Eε4的比值比4.4（95% CI，2.8 - 6.8；P <.001）相比，额外存在1个或2个载脂蛋白Eε4等位基因协同将AD风险增加至比值比9.6（95% CI，4.9 - 18.9；P <.001）。
CYP46影响脑β-淀粉样蛋白负荷、脑脊液中β-淀粉样肽和磷酸化tau水平以及晚发性散发性AD的遗传风险。
