Cerebrospinal fluid tau protein as a biochemical marker for Alzheimer’s disease: a community based follow up study

OBJECTIVES Biochemical markers for Alzheimer’s disease would be of great value, especially to help in diagnosis early in the course of the disease. A pronounced increase in CSF tau protein (CSF-tau) is found in most patients with Alzheimer’s disease. However, the specificity has to be further studied, as an increase in CSF-tau has also been found in other dementias, especially in vascular dementia. As most previous CSF studies have been based on selected inpatients, it was considered of special interest to examine the diagnostic potential of CSF-tau in a community population based sample of consecutive patients with dementia. Such patient material has been examined at the Piteå River Valley Hospital in Northern Sweden since 1986, and includes all those with memory disturbances in the community. The aim was also to study if an increase in CSF-tau is found early in the disease process, and whether CSF-tau changes during the progression of disease. METHODS Participants: Community population based sample of 75 demented patients (43 with Alzheimer’s disease, 21 with vascular dementia, and 11 with mixed Alzheimer’s disease/vascular dementia), 18 healthy subjects, and 18 neurological controls. A follow up investigation (including analysis of a new CSF sample) was performed in all patients after about one year. MAIN OUTCOME MEASURES Concentrations of total (both normal tau and PHF-tau) tau in CSF, clinical measures (duration and severity of dementia), and apoE polymorphism. RESULTS CSF-tau was markedly increased in Alzheimer’s disease, 41/43 (95%) patients had values above the cut off level (mean+2 SD) in controls (306 pg/ml). High CSF-tau concentrations were also found in most patients with vascular dementia, preferentially in patients with vascular dementia without progressive leukoaraiosis on CT, whereas patients with vascular dementia with progressive leukoaraiosis had normal CSF-tau. Concentrations of CSF-tau were stable at one year follow up in both patients with Alzheimer’s disease and patients with vascular dementia, and there was no correlation between CSF-tau and either duration or severity of dementia. CONCLUSIONS The findings confirm the high sensitivity of CSF-tau for the diagnosis of Alzheimer’s disease, but high CSF-tau was also found in vascular dementia, resulting in a lower specificity. However, high CSF-tau is preferentially found in patients with vascular dementia without progressive leukoaraiosis, which may constitute a group with concomitant Alzheimer’s disease pathology. High CSF-tau may be present during the whole course of the disease in Alzheimer’s disease. Possibly, therefore, the same high CSF-tau concentrations may be present before the onset of clinical dementia. Follow up studies on such patients will tell whether analysis of CSF-tau is useful as a biochemical marker for early Alzheimer’s disease.

[1]  D. Galasko,et al.  Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer's disease , 1997, Neurology.

[2]  T. Jones,et al.  Apolipoprotein-E genotyping in diagnosis of Alzheimer's disease , 1996, The Lancet.

[3]  A. Kurz,et al.  Cerebrospinal protein tau is elevated in early Alzheimer's disease , 1996, Neuroscience Letters.

[4]  M. Pericak-Vance,et al.  Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease , 1996, The Lancet.

[5]  K. Jellinger,et al.  Total tau protein immunoreactivity in lumbar cerebrospinal fluid of patients with Alzheimer's disease. , 1996, Journal of neurology, neurosurgery, and psychiatry.

[6]  K. Blennow,et al.  A population-based study of tau protein and ubiquitin in cerebrospinal fluid in 85-year-olds: relation to severity of dementia and cerebral atrophy, but not to the apolipoprotein E4 allele. , 1995, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

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

[8]  J. Trojanowski,et al.  Tau in cerebrospinal fluid: A potential diagnostic marker in Alzheimer's disease , 1995, Annals of neurology.

[9]  R. Wolfert,et al.  Reduction of β‐amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease , 1995 .

[10]  Á. Hernanz,et al.  Tau protein concentrations in cerebrospinal fluid of patients with dementia of the Alzheimer type. , 1995, Journal of neurology, neurosurgery, and psychiatry.

[11]  A. Roses,et al.  ApoE3 binding to tau tandem repeat I is abolished by tau serine262 phosphorylation , 1995, Neuroscience Letters.

[12]  L. Chang,et al.  Tau protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer's disease. , 1995, Annals of clinical and laboratory science.

[13]  T. Kurki,et al.  Clinical characteristics of rapidly progressive leuko‐araiosis , 1995, Acta neurologica Scandinavica.

[14]  J. Growdon,et al.  Cerebrospinal fluid levels of amyloid β‐protein in alzheimer's disease: Inverse correlation with severity of dementia and effect of apolipoprotein e genotype , 1995, Annals of neurology.

[15]  L. Chang,et al.  Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer's disease , 1995, Neurology.

[16]  M. Smith,et al.  Apolipoprotein E interaction with the neurofibrillary tangles and senile plaques in Alzheimer disease: implications for disease pathogenesis. , 1995, Biochemical and biophysical research communications.

[17]  C. Hock,et al.  Increased levels of τ protein in cerebrospinal fluid of patients with alzheimer's disease—correlation with degree of cognitive impairment , 1995, Annals of neurology.

[18]  S. Hirai,et al.  Tau in cerebrospinal fluids: establishment of the sandwich ELISA with antibody specific to the repeat sequence in tau , 1995, Neuroscience Letters.

[19]  Lars Lannfelt,et al.  Increased cerebrospinal fluid tau in patients with Alzheimer's disease , 1995, Neuroscience Letters.

[20]  M. Pericak-Vance,et al.  Apolipoprotein E Is Present in Hippocampal Neurons without Neurofibrillary Tangles in Alzheimer's Disease and in Age-Matched Controls , 1994, Experimental Neurology.

[21]  Margaret A. Pericak-Vance,et al.  Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype , 1994, Experimental Neurology.

[22]  Jan Six,et al.  Detection of Proteins in Normal and Alzheimer's Disease Cerebrospinal Fluid with a Sensitive Sandwich Enzyme‐Linked Immunosorbent Assay , 1993 .

[23]  M. Goedert.  Tau protein and the neurofibrillary pathology of Alzheimer's disease , 1993, Trends in Neurosciences.

[24]  S. Gauthier,et al.  Apolipoprotein E polymorphism and Alzheimer's disease , 1993, The Lancet.

[25]  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.

[26]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[27]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D. Drachman.  New criteria for the diagnosis of vascular dementia , 1993, Neurology.

[29]  Bradley T. Hyman,et al.  Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease , 1992, Neurology.

[30]  Thomas Wisniewski,et al.  Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid , 1992, Neuroscience Letters.

[31]  B. Zimmer,et al.  Index of Authors , 1991, Nutrition Research Reviews.

[32]  E. Otomo,et al.  Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease , 1991, Brain Research.

[33]  Kenneth R. Brizzee,et al.  Neuron numbers and dendritic extent in normal aging and alzheimer's disease , 1987, Neurobiology of Aging.

[34]  Paul D. Coleman,et al.  Neuron numbers and dendritic extent in normal aging and Alzheimer's disease , 1987, Neurobiology of Aging.

[35]  J. Kane,et al.  A Method for the Identification of Apolipoprotein E Isoforms Employing Chemical Precipitation and Flat Bed Isoelectric Focusing in Agarose , 1986, Annals of clinical biochemistry.

[36]  H. Wiśniewski,et al.  Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Gardner,et al.  Statistical guidelines for contributors to medical journals. , 1983, British medical journal.

[38]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[39]  K. Blennow,et al.  Pathogenetic basis of vascular dementia. , 1991, Alzheimer Disease and Associated Disorders.

[40]  H. Wiśniewski,et al.  Abnormal phosphorylation of the microtubule-associated protein? (tau) in Alzheimer cytoskeletal pathology , 1987 .

[41]  Y. Ihara,et al.  Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. , 1986, Journal of biochemistry.