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.

Download full-text


Available from: Douglas Galasko
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.
    Full-text · Article · Aug 2013 · Journal of Neuroimmune Pharmacology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10(-9) for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10(-8) and p = 3.22 × 10(-9) for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10(-8) for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10(-4), 0.039, 4.86 × 10(-5), respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
    Full-text · Article · Apr 2013 · Neuron
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sporadic Alzheimer's disease (AD) is an emerging chronic illness characterized by a progressive pleiotropic pathophysiological mode of actions triggered during the senescence process and affecting the elderly worldwide. The complex molecular mechanisms of AD not only are supported by cholinergic, beta-amyloid, and tau theories but also have a genetic basis that accounts for the difference in symptomatology processes activation among human population which will evolve into divergent neuropathological features underlying cognitive and behaviour alterations. Distinct immune system tolerance could also influence divergent responses among AD patients treated by immunotherapy. The complexity in nature increases when taken together the genetic/immune tolerance with the patient's brain reserve and with neuropathological evolution from early till advance AD clinical stages. The most promising diagnostic strategies in today's world would consist in performing high diagnostic accuracy of combined modality imaging technologies using beta-amyloid 42 peptide-cerebrospinal fluid (CSF) positron emission tomography (PET), Pittsburgh compound B-PET, fluorodeoxyglucose-PET, total and phosphorylated tau-CSF, and volumetric magnetic resonance imaging hippocampus biomarkers for criteria evaluation and validation. Early diagnosis is the challenge task that needs to look first at plausible mechanisms of actions behind therapies, and combining them would allow for the development of efficient AD treatment in a near future.
    Full-text · Article · Feb 2013 · The Scientific World Journal
Show more