Elucidating the mechanisms underlying Alzheimer\u27s disease-associated genetic polymorphisms

Recent genome-wide association studies (GWAS) have yielded a bounty of single nucleotide polymorphisms (SNP)s related to Alzheimer\u27s disease (AD) or conditions associated with AD. Here, we will present several vignettes that illustrate approaches to use these results to clarify AD-related pathways and potential therapeutic

Elucidating the mechanisms underlying Alzheimer's disease-associated genetic polymorphisms

Recent genome-wide association studies (GWAS) have yielded a bounty of single nucleotide polymorphisms (SNP)s related to Alzheimer\u27s disease (AD) or conditions associated with AD. Here, we will present several vignettes that illustrate approaches to use these results to clarify AD-related pathways and potential therapeutic

Home and who: A rhetorical analysis of Rudyard Kipling\u27s Tiger! tiger!\u27 and Letting in the jungle

These stories are representative of an idea that is repeatedly expressed both in the concrete details of Kipling\u27s stories and in the way he uses language. It is possible to see that Kipling, the archetypical man of the empire, may not always have been the empire\u27s man in his work; and causes for that may be found in the alluring, very non-English place he lived in for several years of his youth: India

Isoform of APOE with retained intron 3; quantitation and identification of an associated single nucleotide polymorphism

BACKGROUND: Alleles of apolipoprotein E (APOE) are the major genetic risk factor for late onset Alzheimer\u27s Disease (LOAD). Recently, an APOE splice variant that retains intron 3 (APOE-I3) was identified. To gain insight into the possible role of this isoform in LOAD, we quantified its expression in a cohort of 56 human brain specimens by using quantitative RT-PCR. RESULTS: We found that APOE-I3 generally represents a low percentage (\u3c 0.5%) of overall APOE expression. However, in one specimen, the proportion of APOE-I3 was increased about ~13 fold. This specimen was unique in the cohort for possessing the minor allele of an intron 3 single nucleotide polymorphism (SNP), rs12982192. Additionally, an allelic expression imbalance study indicated that the rs12982192 minor allele was associated with increased APOE-I3 expression. CONCLUSIONS: Overall, we interpret our results as suggesting that APOE-I3 represents a minor portion of APOE expression and that rs12982192 is associated with APOE intron 3 retention. Since the minor allele of this SNP is on the same haplotype as the minor allele of rs429358, which defines the APOE4 allele, we speculate that rs12982192 may reflect a modest loss of mRNA encoding functional APOE4

Method, Composition, and Kit Useful for Treatment of Alzheimer\u27s Disease

The presently-disclosed subject matter includes methods for treating Alzheimer\u27s disease in a subject. The subject can have Alzheimer\u27s diseases, can be identified has being at risk for developing Alzheimer\u27s disease, or both. The method can comprise administering a composition that includes a CD33 inhibitor, which may include a CD33 antibody. In some embodiments the composition can further comprise at least one additional component useful for treating Alzheimer\u27s disease. The presently-disclosed subject matter also includes compositions and kits for treating Alzheimer\u27s disease in a subject

Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer\u27s disease

BACKGROUND: Rheumatoid arthritis (RA) and Alzheimer\u27s disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis. RESULTS: In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p \u3c 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively). CONCLUSIONS: RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression

Genetics of \u3cem\u3ePICALM\u3c/em\u3e Expression and Alzheimer\u27s Disease

Novel Alzheimer\u27s disease (AD) risk factors have been identified by genome-wide association studies. Elucidating the mechanism underlying these factors is critical to the validation process and, by identifying rate-limiting steps in AD risk, may yield novel therapeutic targets. Here, we evaluated the association between the AD-associated polymorphism rs3851179 near PICALM, which encodes a clathrin-coated pit accessory protein. Immunostaining established that PICALM is expressed predominately in microvessels in human brain. Consistent with this finding, PICALM mRNA expression correlated with expression of the endothelial genes vWF and CD31. Additionally, we found that PICALM expression was modestly increased with the rs3851179A AD-protective allele. Analysis of PICALM isoforms found several isoforms lacking exons encoding elements previously identified as critical to PICALM function. Increased expression of the common isoform lacking exon 13 was also associated with the rs3851179A protective allele; this association was not apparent when this isoform was compared with total PICALM expression, indicating that the SNP is associated with total PICALM expression and not this isoform per se. Interestingly, PICALM lacking exons 2–4 was not associated with rs3851179 but was associated with rs592297, which is located in exon 5. Thus, our primary findings are that multiple PICALM isoforms are expressed in the human brain, that PICALM is robustly expressed in microvessels, and that expression of total PICALM is modestly correlated with the AD-associated SNP rs3851179. We interpret these results as suggesting that increased PICALM expression in the microvasculature may reduce AD risk

Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer\u27s disease suggests a role for rs3846662 and \u3cem\u3eHMGCR\u3c/em\u3e splicing in disease risk

BACKGROUND: Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer\u27s disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD. RESULTS: Seventeen non-APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with HMGCR exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with HMGCR exon 13 splicing in liver- and brain-derived cell lines. CONCLUSIONS: Cholesterol-associated SNPs outside of APOE confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with HMGCR exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD

Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the <it>APOE </it>gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD.</p> <p>Results</p> <p>Seventeen non-<it>APOE </it>SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with <it>HMGCR </it>exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with <it>HMGCR </it>exon 13 splicing in liver- and brain-derived cell lines.</p> <p>Conclusions</p> <p>Cholesterol-associated SNPs outside of <it>APOE </it>confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with <it>HMGCR </it>exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD.</p

An Intronic \u3cem\u3ePICALM\u3c/em\u3e Polymorphism, rs588076, Is Associated with Allelic Expression of a \u3cem\u3ePICALM\u3c/em\u3e Isoform

BACKGROUND: Although genome wide studies have associated single nucleotide polymorphisms (SNP)s near PICALM with Alzheimer\u27s disease (AD), the mechanism underlying this association is unclear. PICALM is involved in clathrin-mediated endocytosis and modulates Aß clearance in vitro. Comparing allelic expression provides the means to detect cis-acting regulatory polymorphisms. Thus, we evaluated whether PICALM showed allele expression imbalance (AEI) and whether this imbalance was associated with the AD-associated polymorphism, rs3851179. RESULTS: We measured PICALM allelic expression in 42 human brain samples by using next-generation sequencing. Overall, PICALM demonstrated equal allelic expression with no detectable influence by rs3851179. A single sample demonstrated robust global PICALM allelic expression imbalance (AEI), i.e., each of the measured isoforms showed AEI. Moreover, the PICALM isoform lacking exons 18 and 19 (D18-19 PICALM) showed significant AEI in a subset of individuals. Sequencing these individuals and subsequent genotyping revealed that rs588076, located in PICALM intron 17, was robustly associated with this imbalance in D18-19 PICALM allelic expression (p = 9.54 x 10-5). This polymorphism has been associated previously with systolic blood pressure response to calcium channel blocking agents. To evaluate whether this polymorphism was associated with AD, we genotyped 3269 individuals and found that rs588076 was modestly associated with AD. However, when both the primary AD SNP rs3851179 was added to the logistic regression model, only rs3851179 was significantly associated with AD. CONCLUSIONS: PICALM expression shows no evidence of AEI associated with rs3851179. Robust global AEI was detected in one sample, suggesting the existence of a rare SNP that strongly modulates PICALM expression. AEI was detected for the D18-19 PICALM isoform, and rs588076 was associated with this AEI pattern. Conditional on rs3851179, rs588076 was not associated with AD risk, suggesting that D18-19 PICALM is not critical in AD. In summary, this analysis of PICALM allelic expression provides novel insights into the genetics of PICALM expression and AD risk