SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease

Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
PLoS Genetics (Impact Factor: 7.53). 09/2010; 6(9). DOI: 10.1371/journal.pgen.1001101
Source: PubMed


Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD.

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    • "We have selected a representative from each of these components as CSF guide biomarkers to incorporate into each of our studies: CSF HIV RNA, neopterin and neurofilament light chain (NFL) concentrations. These serve as indicators or vectors of these pathogenetic components; other terms that have been used for these types of biomarkers are orthogonal biomarkers and endophenotypes (Cruchaga et al. 2010; Angel et al. 2012). Table 1 lists these three biomarkers along with other examples from our own previous and ongoing work. "
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    • "Enigmatically, CSF tau levels are normal or low in other tauopathies such as progressive supranuclear palsy, so the precise relationship between the burden of tau pathology as well as the extent of neurodegeneration and the levels of CSF tau remain to be fully clarified (Hu et al., 2011). This notwithstanding , CSF tau levels may be a useful marker to identify genetic variants implicated not only with risk for Alzheimer's disease but also age at onset (Kauwe et al., 2008) or rate of progression (Shoji et al., 1998; Cruchaga et al., 2010). Previous GWAS for CSF tau and ptau levels (Han et al., 2010; Kim et al., 2011) have been conducted in much smaller samples and have shown robust association with markers on chromosome 19 surrounding APOE but failed to detect additional genome-wide significant associations. "
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    • "Furthermore, significant interactions of ApoE4 with SORL1 single nucleotide polymorphisms on Aí µí»½42 cerebrospinal fluid (CSF) indicated the role that SORL1 genetic variants can have in regulating the amyloidogenic pathway [72]. Other methods have examined the relationship between small-nucleotide polymorphism loci in protein phosphatase B and calcium homeostasis modulator 1 (CALHM1), respectively , with AD quantitative biomarkers such as p-tau and Aí µí»½42 CSF or genome-wide association study with MRI brain structure degeneration localized in temporal, parietal, and hippocampal regions [73] [74] [75] [76] [77]. Histopathological aromatic dyes staining using Thioflavin S but especially Congo red is the gold standard for diagnosing amyloid plaques because it only binds aggregated í µí»½sheets [78] [79], and postmortem clinical diagnosis is still regarded as the gold standard for definitive diagnostic of AD. "
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