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

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Neurogenetics (Impact Factor: 2.88). 10/2008; 10(1):13-7. DOI: 10.1007/s10048-008-0150-4
Source: PubMed


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 ( ) 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.

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    • "We found that the ACE II genotype was associated with reduced ACE protein level in the CSF (Miners et al., 2010b). Other studies showed significant association between ACE variants and Aβ 1−42 concentration or the Aβ 1−42 :Aβ 1−40 ratio in the CSF (Lehmann et al., 2005; Kauwe et al., 2009). These studies suggested that an association between the ACE polymorphism and AD might be mediated through reduced ACE-mediated proteolysis of Aβ. "
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    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. DOI:10.3389/fnagi.2014.00238 · 4.00 Impact Factor
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    • "Few studies have examined the association between ACE and AD biomarkers in CSF [13,14]. Results on the association between the I-allele, or haplotypes, of the ACE gene, which have been associated with lower ACE levels, and CSF Aβ were inconclusive [13,14]. Further, one small-scale study found that administration of an ACE inhibitor did not influence AD biomarkers in CSF [15]. "
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    ABSTRACT: Introduction Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau). Methods We included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid β1–42, tau and ptau (pg/ml) in CSF. Results Cross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively. Conclusions These results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD.
    Alzheimer's Research and Therapy 05/2014; 6(3):27. DOI:10.1186/alzrt257 · 3.98 Impact Factor
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    • "The ability to measure Aβ levels in the serum and cerebrospinal fluid (CSF) of AD patients and their relatives [13], and the determination that Aβ levels are heritable [14] enabled the first studies utilizing Aβ levels as endophenotypes in genetic studies that discovered genetic loci and variants influencing AD risk and Aβ [8, 15–17]. This was followed by investigations of CSF Aβ [18] and tau levels [19] as endophenotypes in AD genetics studies. Third, the availability of prospective, elderly cohorts with rich clinical, neurocognitive and neuroimaging measures [20–22], knowledge that many of these measures are heritable [6, 7, 23], and detection of preclinical changes in these measures (reviewed [24••]) advocate their use as endophenotypes in genetic studies of AD. "
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    ABSTRACT: Uncovering the genetic risk and protective factors for complex diseases is of fundamental importance for advancing therapeutic and biomarker discoveries. This endeavor is particularly challenging for neuropsychiatric diseases where diagnoses predominantly rely on the clinical presentation, which may be heterogeneous, possibly due to the heterogeneity of the underlying genetic susceptibility factors and environmental exposures. Although genome-wide association studies of various neuropsychiatric diseases have recently identified susceptibility loci, there likely remain additional genetic risk factors that underlie the liability to these conditions. Furthermore, identification and characterization of the causal risk variant(s) in each of these novel susceptibility loci constitute a formidable task, particularly in the absence of any prior knowledge about their function or mechanism of action. Biologically relevant, quantitative phenotypes, i.e., endophenotypes, provide a powerful alternative to the more traditional, binary disease phenotypes in the discovery and characterization of susceptibility genes for neuropsychiatric conditions. In this review, we focus on Alzheimer's disease (AD) as a model neuropsychiatric disease and provide a synopsis of the recent literature on the use of endophenotypes in AD genetics. We highlight gene expression, neuropathology and cognitive endophenotypes in AD, with examples demonstrating the utility of these alternative approaches in the discovery of novel susceptibility genes and pathways. In addition, we discuss how these avenues generate testable hypothesis about the pathophysiology of genetic factors that have far-reaching implications for therapies.
    03/2013; 1(1):39-51. DOI:10.1007/s40142-013-0007-5
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