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

English version České info

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 (ptau₁₈₁) 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 ptau₁₈₁ levels in two independent CSF series . 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 . Our analyses suggest that genetic variants associated with CSF ptau₁₈₁ levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ₄₂ 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 Aβ₄₂ levels. Finally, we believe genome-wide association studies of CSF tau/ptau₁₈₁ levels should identify novel genetic variants which will likely influence rate of progression of AD.

Vyšlo v časopise: SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001101
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001101

Souhrn

Zdroje

1. HaroldD

AbrahamR

HollingworthP

SimsR

GerrishA

2009 Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41 1088 1093

2. LambertJC

HeathS

EvenG

CampionD

SleegersK

2009 Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41 1094 1099

3. ChambersJC

ZhangW

LiY

SehmiJ

WassMN

2009 Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet 41 1170 1172

4. BenyaminB

FerreiraMA

WillemsenG

GordonS

MiddelbergRP

2009 Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet 41 1173 1175

5. SoranzoN

SpectorTD

ManginoM

KuhnelB

RendonA

2009 A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 41 1182 1190

6. GaneshSK

ZakaiNA

van RooijFJ

SoranzoN

SmithAV

2009 Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 41 1191 1198

7. RivadeneiraF

StyrkarsdottirU

EstradaK

HalldorssonBV

HsuYH

2009 Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41 1199 1206

8. CohenJC

KissRS

PertsemlidisA

MarcelYL

McPhersonR

2004 Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305 869 872

9. CohenJC

PertsemlidisA

FahmiS

EsmailS

VegaGL

2006 Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proc Natl Acad Sci U S A 103 1810 1815

10. RomeoS

PennacchioLA

FuY

BoerwinkleE

Tybjaerg-HansenA

2007 Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 39 513 516

11. RomeoS

YinW

KozlitinaJ

PennacchioLA

BoerwinkleE

2009 Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest 119 70 79

12. PriceJL

MorrisJC

1999 Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 45 358 368

13. FaganAM

HeadD

ShahAR

MarcusD

MintunM

2009 Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 65 176 183

14. FaganAM

MintunMA

MachRH

LeeSY

DenceCS

2006 Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59 512 519

15. MorrisJC

RoeCM

XiongC

FaganAM

GoateAM

2010 APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 67 122 131

16. HanssonO

ZetterbergH

BuchhaveP

AndreassonU

LondosE

2007 Prediction of Alzheimer's disease using the CSF Abeta42/Abeta40 ratio in patients with mild cognitive impairment. Dement Geriatr Cogn Disord 23 316 320

17. KapakiEN

ParaskevasGP

TzerakisNG

SfagosC

SeretisA

2007 Cerebrospinal fluid tau, phospho-tau181 and beta-amyloid1-42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer's disease. Eur J Neurol 14 168 173

18. FaganAM

RoeCM

XiongC

MintunMA

MorrisJC

2007 Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 64 343 349

19. NoguchiM

YoshitaM

MatsumotoY

OnoK

IwasaK

2005 Decreased beta-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration. J Neurol Sci 237 61 65

20. IkonomovicMD

KlunkWE

AbrahamsonEE

MathisCA

PriceJC

2008 Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain 131 1630 1645

21. JagustWJ

LandauSM

ShawLM

TrojanowskiJQ

KoeppeRA

2009 Relationships between biomarkers in aging and dementia. Neurology 73 1193 1199

22. HesseC

RosengrenL

AndreasenN

DavidssonP

VandersticheleH

2001 Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 297 187 190

23. OstM

NylenK

CsajbokL

OhrfeltAO

TullbergM

2006 Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 67 1600 1604

24. BuergerK

EwersM

PirttilaT

ZinkowskiR

AlafuzoffI

2006 CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 129 3035 3041

25. UrakamiK

WadaK

AraiH

SasakiH

KanaiM

2001 Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy. J Neurol Sci 183 95 98

26. AraiH

MorikawaY

HiguchiM

MatsuiT

ClarkCM

1997 Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology. Biochem Biophys Res Commun 236 262 264

27. KauweJS

CruchagaC

MayoK

FenoglioC

BertelsenS

2008 Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition. Proc Natl Acad Sci U S A 105 8050 8054

28. KauweJS

JacquartS

ChakravertyS

WangJ

MayoK

2007 Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann Neurol 61 446 453

29. KauweJS

WangJ

MayoK

MorrisJC

FaganAM

2009 Alzheimer's disease risk variants show association with cerebrospinal fluid amyloid beta. Neurogenetics 10 13 17

30. Sato-HaradaR

OkabeS

UmeyamaT

KanaiY

HirokawaN

1996 Microtubule-associated proteins regulate microtubule function as the track for intracellular membrane organelle transports. Cell Struct Funct 21 283 295

31. WangJZ

Grundke-IqbalI

IqbalK

2007 Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25 59 68

32. Spires-JonesTL

StoothoffWH

de CalignonA

JonesPB

HymanBT

2009 Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci 32 150 159

33. SniderBJ

FaganAM

RoeC

ShahAR

GrantEA

2009 Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Arch Neurol 66 638 645

34. WebsterJA

GibbsJR

ClarkeJ

RayM

ZhangW

2009 Genetic control of human brain transcript expression in Alzheimer disease. Am J Hum Genet 84 445 458

35. BertramL

McQueenMB

MullinK

BlackerD

TanziRE

2007 Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39 17 23

36. YuDY

LuoJ

BuF

SongGJ

ZhangLQ

2006 Inhibition of calcineurin by infusion of CsA causes hyperphosphorylation of tau and is accompanied by abnormal behavior in mice. Biol Chem 387 977 983

37. LuoJ

MaJ

YuDY

BuF

ZhangW

2008 Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain. Brain Res Bull 76 464 468

38. GarverTD

KincaidRL

ConnRA

BillingsleyML

1999 Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231. Mol Pharmacol 55 632 641

39. LadnerCJ

CzechJ

MauriceJ

LorensSA

LeeJM

1996 Reduction of calcineurin enzymatic activity in Alzheimer's disease: correlation with neuropathologic changes. J Neuropathol Exp Neurol 55 924 931

40. MorganAR

TuricD

JehuL

HamiltonG

HollingworthP

2007 Association studies of 23 positional/functional candidate genes on chromosome 10 in late-onset Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 144B 762 770

41. BergL

McKeelDWJr

MillerJP

StorandtM

RubinEH

1998 Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 55 326 335

42. McKhannG

DrachmanD

FolsteinM

KatzmanR

PriceD

1984 Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34 939 944

43. BraakH

BraakE

1991 Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82 239 259

44. MullerPY

JanovjakH

MiserezAR

DobbieZ

2002 Processing of gene expression data generated by quantitative real-time RT-PCR. Biotechniques 32 1372 1374, 1376, 1378–1379

45. StoothoffWH

JohnsonGV

2005 Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta 1739 280 297

46. YuzwaSA