Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants

Neurofilament light (NFL) proteins in cerebrospinal fluid (CSF) are a marker of neuronal damage, especially subcortical axonal injury and white matter disease. Subjects with Alzheimer's disease (AD) have shown elevated levels of CSF NFL as compared to controls. However, the presence of the APOE ε4 allele, an established risk factor for AD, was not found to associate with higher CSF NFL concentrations. We examined whether TOMM40 variants, which have been reported to influence age of onset of AD and are in linkage disequilibrium with APOE, have an effect on CSF NFL levels, in 47 healthy, cognitively intact individuals with or without APOE ε4. Our results show that the presence of APOE ε4 alone does not affect CSF NFL levels significantly; however APOE and TOMM40 appear to interact. Subjects with APOE ε4 have higher CSF NFL levels than non-ε4 carriers, only when they do not carry a short poly-T variant of TOMM40, which is associated with later age of onset of AD, and may act as protective against the dose effect of ε4.

[1]  R. Friede,et al.  Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice , 1970, The Anatomical record.

[2]  Andrew Rutherford,et al.  ANOVA and ANCOVA: A GLM Approach , 2011 .

[3]  M. Mesulam,et al.  Cholinergic nucleus basalis tauopathy emerges early in the aging‐MCI‐AD continuum , 2004, Annals of neurology.

[4]  N. Norgren,et al.  Elevated neurofilament levels in neurological diseases , 2003, Brain Research.

[5]  K. Blennow,et al.  Neurochemical aftermath of amateur boxing , 2006, Archives of neurology.

[6]  K. Blennow,et al.  Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD , 2000, Neurology.

[7]  C. Teunissen,et al.  The neurofilament light chain is not stable in vitro , 2011, Annals of neurology.

[8]  K. Blennow,et al.  Neurofilament protein levels in CSF are increased in dementia , 1999, Neurology.

[9]  J. Nierenberg,et al.  Cerebrospinal fluid cortisol concentrations in healthy elderly are affected by both APOE and TOMM40 variants , 2012, Psychoneuroendocrinology.

[10]  A. Roses,et al.  Genetic variation at a single locus and age of onset for Alzheimer's disease , 2010, Alzheimer's & Dementia.

[11]  J W Griffin,et al.  Neurofilament gene expression: a major determinant of axonal caliber. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Scheltens,et al.  CSF Neurofilaments in Frontotemporal Dementia Compared with Early Onset Alzheimer’s Disease and Controls , 2007, Dementia and Geriatric Cognitive Disorders.

[13]  C. Geula,et al.  Cholinergic Neuronal and Axonal Abnormalities Are Present Early in Aging and in Alzheimer Disease , 2008, Journal of neuropathology and experimental neurology.

[14]  A. Roses,et al.  TOMM40, APOE, and age of onset of Alzheimer's disease , 2010, Alzheimer's & Dementia.

[15]  K. Blennow,et al.  TOMM40 poly-T Variants and Cerebrospinal Fluid Amyloid Beta Levels in the Elderly , 2011, Neurochemical Research.

[16]  H. Zetterberg,et al.  Levels of brain related proteins in cerebrospinal fluid: an aid in the differential diagnosis of parkinsonian disorders. , 2009, Parkinsonism & related disorders.

[17]  K. Blennow,et al.  Neurofilament protein in cerebrospinal fluid: A marker of white matter changes , 2001, Journal of neuroscience research.

[18]  K. Blennow,et al.  Is there a CSF biomarker profile related to depression in elderly women? , 2010, Psychiatry Research.

[19]  M N Rossor,et al.  A Systematic Review and Meta-Analysis of CSF Neurofilament Protein Levels as Biomarkers in Dementia , 2007, Neurodegenerative Diseases.

[20]  K. Blennow.  Dementia in 2010: Paving the way for Alzheimer disease drug development , 2011, Nature Reviews Neurology.

[21]  W. F. Abdo,et al.  CSF neurofilament proteins levels are elevated in sporadic Creutzfeldt-Jakob disease. , 2010, Journal of Alzheimer's disease : JAD.

[22]  K. Blennow,et al.  Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? , 1995, Molecular and chemical neuropathology.

[23]  D. Selkoe.  Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[24]  I. Grundke‐Iqbal,et al.  Elevated levels of phosphorylated neurofilament proteins in cerebrospinal fluid of Alzheimer disease patients , 2002, Neuroscience Letters.

[25]  J. Fleming,et al.  A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking , 2009, Neurology.

[26]  K. Blennow,et al.  Subcortical Vascular Dementia Biomarker Pattern in Mild Cognitive Impairment , 2009, Dementia and Geriatric Cognitive Disorders.

[27]  C. Wikkelsø,et al.  Patients with Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases Have Increased Levels of Neurofilament Protein in CSF , 1996, Journal of neurochemistry.

[28]  M. Weiner,et al.  Cerebrospinal fluid and plasma biomarkers in Alzheimer disease , 2010, Nature Reviews Neurology.

[29]  H. Buschke.  RETRIEVAL IN VERBAL LEARNING , 1974 .

[30]  M. L. Schmidt,et al.  Distribution of tau proteins in the normal human central and peripheral nervous system. , 1989, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[31]  K. Blennow,et al.  Lower CSF amyloid beta peptides and higher F2-isoprostanes in cognitively intact elderly individuals with major depressive disorder. , 2012, The American journal of psychiatry.

[32]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[33]  J. O'Brien,et al.  Genetic Associations of Autopsy-Confirmed Vascular Dementia Subtypes , 2011, Dementia and Geriatric Cognitive Disorders.

[34]  M. Verbeek,et al.  An enzyme immunoassay to quantify neurofilament light chain in cerebrospinal fluid. , 2005, Journal of immunological methods.

[35]  Y. Pijnenburg,et al.  CSF neurofilament proteins in the differential diagnosis of dementia , 2007, Journal of Neurology, Neurosurgery & Psychiatry.

[36]  A D Roses,et al.  A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease , 2009, The Pharmacogenomics Journal.

[37]  K. Blennow,et al.  Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization , 2000, Neuroscience Letters.