Late-onset Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder. In addition to the apolipoprotein E (APOE) gene on chromosome 19, linkage studies suggest the existence of multiple susceptibility genes for late-onset AD. Genome-wide linkage and chromosome-12-specific linkage studies have identified a broad 50-cM pericentromeric region between 12p12 and 12q13 among non- APOE*4 carriers. Some studies have implicated the alpha2-macroglobulin (A2M) gene in 12p12 as being the chromosome 12 gene, but the results are equivocal. Because of its close proximity to the A2M gene and because it is abundantly expressed in the brain, we reasoned that the oxidized LDL-receptor 1 (OLR1) gene could be a candidate gene for AD. We screened all exons and intron-exon boundaries of the OLR1 gene for new mutations and identified three novel sequence variations in intron 4, intron 5, and the 3' untranslated region (UTR). Pair-wise comparisons between the three polymorphic sites revealed significant linkage disequilibrium ( P<0.0001). We screened more than 800 late-onset AD cases and more than 700 controls for the three OLR1 polymorphisms. All polymorphisms showed significant association with AD after stratification by APOE*4, with the strongest effect being observed for the 3'UTR polymorphism among non- APOE*4 (odds ratio 0.658; 95% confidence interval: 0.47-0.92; P=0.014) and APOE*4 (odds ratio 1.72; 95% confidence interval: 1.07-2.78; P=0.025) carriers. DNA-protein binding assay with nuclear protein extracts from neuroblastoma cells indicated that the OLR1/3'UTR polymorphism affects the binding of a transcription factor in an allele-dependent manner. Our data suggest that genetic variation in the OLR1 gene may modify the risk of AD in an APOE*4-dependent fashion.

Objective: To explore the association between APOE*4 and pathologically confirmed cases of the Lewy body (LB) variant of Alzheimer disease (AD). Methods: With use of α-synuclein (AS) immunohistochemistry, LBs were detected in 74 of 131 (56.5%) of the AD + LB cases; the remaining 57 cases (43.5%) did not have LBs. Results: There were no differences in gender or age between Caucasian subjects with AD + LB or AD alone or control subjects. The APOE*4 allele frequency was highest in the AD + LB group (47.3%; 95% CI = 37.8 to 57.0%), intermediate in the AD-alone group (35.1%; 95% CI = 25.3 to 46.3%), and lowest in the control group (14.2%; 95% CI = 10.5 to 18.9%). With use of logistic regression analysis, the odds of having AD + LB vs AD alone were 2.1-fold (95% CI = 1.0 to 4.5, p = 0.055) greater in persons with an APOE*4 allele than in those without

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Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder. To date, apolipoprotein E (apoE) is the only established susceptibility gene for late-onset AD. ApoE accounts for less than 50% of the risk of AD, indicating the presence of other unknown susceptibility loci. Linkage studies have indicated chromosome 12 as the most likely location for another late-onset AD locus. We examined seven polymorphisms in five candidate genes located in and around the linkage peaks on chromosome 12 in 564 cases and 523 controls. The genes included complement component 1R (C1R), vitamin D receptor (VDR), scavenger-receptor B1 (SR-B1), low-density lipoprotein receptor related protein 1 (LRP1), and transcription factor LBP-1c/CP2/LSF. We found no association with C1R, VDR, SR-B1, and LRP1 polymorphisms. However, the frequency of the A allele of the 3' (untranslated region) UTR LBP-1c/CP2/LSF polymorphism was higher in controls than cases (0.071 vs. 0.051; P = 0.042) with an adjusted odds ratio (OR) of 0.65 (95% confidence interval [CI]: 0.43-0.96; P = 0.0498). Our data suggest that the LBP-1c/CP2/LSF polymorphism may have a moderate protective effect against the risk of AD.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular neuritic plaques and intracellular neurofibrillary tangles in brain parenchyma. Alpha-1-antichymotrypsin (ACT) is a component of plaque cores, can bind to Abeta, and has been proposed as a possible candidate gene for AD susceptibility. The genetic association between the ACT codon -17*A allele of the signal peptide polymorphism and AD has been shown in some, but not in all studies. One hypothesis is that the ACT codon -17*A allele is in linkage disequilibrium with unknown functional mutation(s) in the ACT gene. This study was undertaken to identify new mutation(s) in the ACT gene by PCR-SSCP-sequencing and, in conjunction with known mutations, to assess their role in affecting the risk of AD. A total of seven new point mutations were observed: 5'UTR(A-->G), Asp128Asn(G-->A), Ser250Ser(C-->T), Leu301Pro(T-->C), Thr324Thr(A-->G), G-->A in intron 4, and 3'UTR C-->A. Of these, mutations at codon 250, codon 324, intron 4 and 3'UTR showed a frequency of 1% or more. Of the known mutations, Thr-17Ala(A-->G), Lys76Lys(A-->G) and Leu241Leu(G-->A) occur at a polymorphic level. The ACT codon -17*A allele was associated with increased risk of AD (OR for AA vs TT: 1.71; 95% CI: 1.16-2.53; P=0.007), especially in the presence of the APOE*4 allele (OR for AA vs TT: 2.35; 95% CI: 1.13-4.85; P=0.02). The codon 241*A allele and the codon 250*T allele were associated with protective effects against AD (OR: 0.36; 95% CI: 0.13-0.86; P=0.02) (OR:0.39; 95% CI: 0.18-0.85; P=0.02). irrespective of the APOE*4 status. The codon 324*G allele was associated with a marginal protective effect (OR:0.57; 95% CI: 0.26-1.26; P=0.17). While the codon 241*A allele was in linkage disequilibrium with the codon -17*A allele, the codon 250*T and codon 324*G alleles were non-randomly associated with the codon -17*T allele. In contrast, the codon 76*G (OR:1.34; 95% CI: 0.92-1.95; P=0.13), codon 227*G (OR:3.96; 95% CI: 0.83-18.8; P=0.08) and intron 4*G (OR:1.47; 95% CI: 0.88-2.29; P=0.15) alleles were associated with a modest risk of AD, and all were in linkage disequilibrium with the codon -17*A allele. EH-based haplotype analysis showed that certain haplotypes are associated with either higher or lower risk of AD. Our data indicate that the ACT gene harbors several potentially important variable sites, which are associated with either an increased or decreased risk of AD. The non-random combination of risk and protective alleles may explain, in part, why the association studies regarding the ACT codon -17*A have been inconsistent, especially if the frequency of other ACT mutations varies between populations.