Alpha-2 macroglobulin is genetically associated with Alzheimer disease

Blacker, Deborah; Wilcox, Marsha; Laird, Nan M.; Rodes, Linda; Horvath, Steven M.; Go, Rodney C.P.; Perry, Rodney T.; Watson, Bracie; Bassett, Susan Spear; McInnis, Melvin G.; Albert, Marilyn; Hyman, Bradley T.; Tanzi, Rudolph E.

doi:10.1038/1243

Cited by 613 publications

(304 citation statements)

References 29 publications

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“…Previous studies have indicated that there may be alterations in the levels of proteins that attenuate Ab fibrillization, namely a2M 155 and SAP 156 in AD patients, although there are also conflicting data on this issue. It should be noted that polymorphism in the a2M gene may be associated with AD risk in some populations and may be influenced by family history (for example references [157][158][159][160][161][162] ), although these findings are controversial. Decreased SAP levels have also been correlated with impaired cognitive performance in aged individuals 163 and in clinically diagnosed AD.…”

Section: Ab-binding Proteins In Blood Plasmamentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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Section: Ab-binding Proteins In Blood Plasmamentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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“…Two candidate genes in the region, alpha-2-macroglobulin (A2M [MIM 103950]) and the low-density lipoprotein receptor-related protein (LRP1 [MIM 107770]), have been the target of investigations, but without consistent results. 16,36,[42][43][44][45] Saunders et al, 46 using the larger NIMH samples, identified several haplotypes that showed an association with AD, suggesting that there may be a gene-either A2M or one nearby-that may confer a modest effect toward AD.…”

Section: Discussionmentioning

confidence: 99%

Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics

et al. 2004

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Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the lateonset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly lateonset AD. We observed the strongest support for linkage on 18q (LOD ¼ 3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P ¼ 0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P ¼ 0.000486) to 2.1 (P ¼ 0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18q.

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“…Strong evidence indicated that additional risk genes exist on chromosome 12 for AD (Blacker et al 1998;Hollenbach et al 1998;Poduslo and Yin 2001;LuedeckingZimmer et al 2003;Beecham et al 2009). The VDR gene is very close to this region and our earlier study provided the first evidence for a possible genetic association between AD and VDR (Gezen-Ak et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor Gene Haplotype Is Associated with Late-Onset Alzheimer's Disease

Gezen-Ak

Dursun

Bılgıç

et al. 2012

Tohoku J. Exp. Med.

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Vitamin D 3 is a neurosteroid that mediates its effects via the vitamin D receptor (VDR). The VDR gene is located on chromosome 12q13 and consists of 9 exons. VDR contains the DNA-binding site encoded by exons 2 and 3 and the ligand-binding site encoded by exons 4 -9. Our earlier study showed that the ApaI polymorphic site of the VDR gene is associated with late-onset Alzheimer's disease (AD). Here, we investigated the association between additional polymorphisms of the VDR gene and AD using the same samples. Two single nucleotide polymorphisms (SNPs) in intron 8 (BsmI and Tru9I polymorphisms) and one in exon 2 (FokI polymorphism) of the VDR gene were examined in up to 108 AD patients and 115 age-matched controls. Genotypes were determined with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Haplotype analysis also included the previously studied polymorphic sites that were recognized by TaqI (in exon 9) and ApaI (in intron 8) restriction enzymes. There was no significant difference between AD patients and controls when their genotypes for BsmI, Tru9I and FokI polymorphic sites were compared. However, the frequency of "TaubF" haplotype (alleles of TaqI, ApaI, Tru9I, BsmI and FokI, respectively), which was determined by analyzing 5 polymorphisms together, was significantly higher in the AD patient group, suggesting that this haplotype is a risk factor in AD. Our results point out a possible link between AD and certain VDR polymorphisms and indicate that individuals with these polymorphisms might be vulnerable to AD.

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Alpha-2 macroglobulin is genetically associated with Alzheimer disease

Cited by 613 publications

References 29 publications

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics

Vitamin D Receptor Gene Haplotype Is Associated with Late-Onset Alzheimer's Disease

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