Article

Alzheimer's disease risk variants show association with cerebrospinal fluid amyloid beta.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Neurogenetics (Impact Factor: 2.66). 10/2008; 10(1):13-7. DOI: 10.1007/s10048-008-0150-4
Source: PubMed

ABSTRACT The use of quantitative endophenotypes in genetic studies may provide greater power, allowing for the use of powerful statistical methods and a biological model for the effects of the disease-associated genetic variation. Cerebrospinal fluid (CSF) amyloid beta (Abeta) levels are promising endophenotypes for late-onset Alzheimer's disease (LOAD) and show correlation with LOAD status and Abeta deposition. In this study, we investigated 29 single nucleotide polymorphisms (SNPs) positive in AlzGene ( http://www.alzgene.org ) meta-analyses, for association with CSF Abeta levels in 313 individuals. This study design makes it possible to replicate reported LOAD risk alleles while contributing novel information about the mechanism by which they might affect that risk. Alleles in ACE, APOE, BDNF, DAPK1, and TF are significantly associated with CSF Abeta levels. In vitro analysis of the TF SNP showed a change in secreted Abeta consistent with the CSF phenotype and known Alzheimer's disease variants, demonstrating the utility of this approach in identifying SNPs that influence risk for disease via an Abeta-related mechanism.

0 Bookmarks
 · 
103 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.
    PLoS Genetics 10/2014; 10(10):e1004758. · 8.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Aβ-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), and angiotensin-converting enzyme (ACE) reduce Aβ levels and protect against cognitive impairment in mouse models of AD. In post-mortem human brain tissue we have found that the activity of these Aβ-degrading enzymes rise with age and increases still further in AD, perhaps as a physiological response that helps to minimize the build-up of Aβ. ECE-1/-2 and ACE are also rate-limiting enzymes in the production of endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictors, increases in the levels of which are likely to contribute to reduced blood flow in AD. This review considers the possible interdependence between Aβ-degrading enzymes, ischemia and Aβ in AD: ischemia has been shown to increase Aβ production both in vitro and in vivo, whereas increased Aβ probably enhances ischemia by vasoconstriction, mediated at least in part by increased ECE and ACE activity. In contrast, NEP activity may help to maintain cerebral perfusion, by reducing the accumulation of Aβ in cerebral blood vessels and lessening its toxicity to vascular smooth muscle cells. In assessing the role of Aβ-degrading proteases in the pathogenesis of AD and, particularly, their potential as therapeutic agents, it is important to bear in mind the multifunctional nature of these enzymes and to consider their effects on other substrates and pathways.
    Frontiers in Aging Neuroscience 09/2014; 6:238. · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a clinically heterogeneous neurodegenerative disease with a strong genetic component. Several genes have been associated with AD risk for nearly 20 years. However, it was not until the recent technological advances that allow for the analysis of millions of polymorphisms in thousands of subjects that we have been able to advance our understanding of the genetic complexity of AD susceptibility. Genome-wide association studies and whole-exome and whole-genome sequencing have revealed more than 20 loci associated with AD risk. These studies have provided insights into the molecular pathways that are altered in AD pathogenesis, which have, in turn, provided insight into novel therapeutic targets.
    Neuron 07/2014; 83(1):11-26. · 15.77 Impact Factor

Full-text (2 Sources)

Download
50 Downloads
Available from
May 27, 2014