Alzheimer’s disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some samples.
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We thank Ms. Esmeralda Gruber and Ms. Christin Wilde for patient care and sampling. This work was supported by grants of the Hartmann Müller-Stiftung für Medizinische Forschung to M. A. W. (983), of the Julius Klaus-Stiftung to M. A. W and A.P., by the Swiss National Science Foundation (PP00B-68859) and the Novartis Stiftung to A. P., by the National Center for Competence in Research (NCCR) “Neuronal Plasticity and Repair”, by the Polish Ministry of Science (PBZ-KBN-124/P05/2004), by the Fund of Scientific Research-Flanders (FWO-F), and by the EU APOPIS program (contract LSHM-CT-2003-503330). K. S. is a postdoctoral fellow and N. B. a doctoral fellow of the FWO-F. The study complies with the current law of the countries in which it was performed.
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Wollmer, M.A., Sleegers, K., Ingelsson, M. et al. Association study of cholesterol-related genes in Alzheimer’s disease. Neurogenetics 8, 179–188 (2007). https://doi.org/10.1007/s10048-007-0087-z