Original Articles| Volume 46, ISSUE 6, P750-755, September 15, 1999

Longitudinal stability of CSF tau levels in Alzheimer patients


      Background: Antemortem levels of tau in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients have repeatedly been demonstrated to be elevated when compared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease.
      Methods: We have followed 29 mild-to-moderately affected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and conclusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsorbent assay (ELISA) using two monoclonal antibodies.
      Results: Despite significant changes in the clinical measures consistent with progression of the disease, no significant overall change in CSF tau levels (548 ± 355 vs. 557±275 pg/mL, NS) was observed. None of the clinical variables was significantly correlated with either baseline measures of CSF tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype.
      Conclusions: These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness.


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        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. Third Edition, Revised. American Psychiatric Association, Washington1987
        • Andreasen N
        • Vanmechelen E
        • Van de Voorde A
        Cerebrospinal fluid tau protein as a marker for Alzheimer’s disease.
        J Neurol Neurosurg Psychiatry. 1998; 64: 298-305
        • Arai H
        • Higuchi S
        • Sasaki H
        Apolipoprotein E genotyping and cerebrospinal fluid tau protein.
        Gerontology. 1997; 43: 2-10
        • Arai H
        • Terajima M
        • Miura M
        • et al.
        Tau in cerebrospinal fluid.
        Ann Neurol. 1995; 38: 649-652
        • Baumann K
        • Mandelkow E.-M
        • Biernat J
        • et al.
        Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5.
        FEBS Lett. 1993; 336: 417-424
        • Blomberg M
        • Jensen M
        • Basun H
        • et al.
        Increasing cerebrospinal fluid tau levels in a subgroup of Alzheimer patients with apolipoprotein E allele E4 during 14 months follow-up.
        Neurosci Lett. 1996; 214: 163-166
        • DeKosky S.T
        • Harbaugh R.E
        • Schmitt F.A
        • et al.
        Cortical biopsy in Alzheimer’s disease.
        Ann Neurol. 1992; 32: 625-632
        • Folstein M.F
        • Folstein S.E
        • McHugh P.R
        “Mini-mental state”.
        J Psychiatry Res. 1975; 12: 189-198
        • Galasko D
        • Chang L
        • Motter R
        • et al.
        High cerebrospinal fluid tau and low amyloid Beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype.
        Arch Neurol. 1998; 55: 937-945
        • Galasko D
        • Clark C
        • Chang L
        • et al.
        Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer’s disease.
        Neurology. 1997; 48: 632-635
        • Galasko D
        • Hansen L
        • Vigo-Pelfrey C
        • et al.
        Antemortem CSF Tau is related to neuronal pathology at autopsy in Alzheimer’s disease.
        Soc Neurosci Abstr. 1995; 21: 581
        • Ghanbari H.A
        • Miller B.E
        • Haigler H.J
        • et al.
        Biochemical assay of Alzheimer’s disease—associated protein(s) in human brain tissue. A clinical study.
        JAMA. 1990; 263: 2907-2910
        • Goedert M
        • Jakes R
        • Spillantini M.G
        • et al.
        Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans.
        Nature. 1996; 383: 550-553
        • Golombowski S
        • Muller-Spahn F
        • Romig H
        • et al.
        Dependence of cerebrospinal fluid tau protein levels on apolipoprotein E4 allele frequency in patients with Alzheimer’s disease.
        Neurosci Lett. 1997; 225: 213-215
        • Hock C
        • Golombowski S
        • Naser W
        • et al.
        Increased levels of tau protein in cerebrospinal fluid of patients with Alzheimer’s disease—correlation with degree of cognitive impairment.
        Ann Neurol. 1995; 37: 414-415
        • Hughes C.P
        • Berg L
        • Danziger W.L
        • et al.
        A new clinical scale for the staging of dementia.
        Br J Psychiatry. 1982; 140: 566-572
        • Jensen M
        • Basun H
        • Lannfelt L
        Increased cerebrospinal fluid tau in patients with Alzheimer’s disease.
        Neurosci Lett. 1995; 186: 189-191
        • Johnson G.V.W
        • Seubert P
        • Cox T.M
        • et al.
        The τ protein in human cerebrospinal fluid in Alzheimer’s disease consists of proteolytically derived fragments.
        Int J Neurochem. 1998; 68: 430-433
        • Kanai M
        • Matsubara E
        • Isoe K
        • et al.
        Longitudinal study of cerebrospinal fluid levels of tau, abeta1–40, and abeta1–42(3) in Alzheimer’s disease.
        Ann Neurol. 1998; 44: 17-26
        • Khatoon S
        • Grundke-Iqbal I
        • Iqbal K
        Brain levels of microtubule-associated protein τ are elevated in Alzheimer’s disease.
        J Neurochem. 1992; 59: 750-753
        • Lehtimäki T
        • Moilanen T
        • Viikari J
        • et al.
        Apolipoprotein E phenotypes in Finnish youths.
        J Lipid Res. 1990; 31: 487-495
        • Lehtimäki T
        • Pirttila T
        • Mehta P.D
        • et al.
        Apolipoprotein E (apoE) polymorphism and its influence on ApoE concentrations in the cerebrospinal fluid in Finnish patients with Alzheimer’s disease.
        Hum Genet. 1995; 95: 39-42
        • Mandelkow E.-M
        • Mandelkow E
        Tau as a marker for Alzheimer’s disease.
        Trends Biochem Sci. 1993; 18: 480-483
        • McKeith I.G
        • Galasko D
        • Kosaka K
        • et al.
        Consensus guidelines international workshop for the clinical and pathological diagnosis of dementia with Lewy bodies (DLB).
        Neurology. 1996; 47: 1113-1124
        • McKhann G
        • Drachman D
        • Folstein M
        • et al.
        Clinical diagnosis of Alzheimer’s disease.
        Neurology. 1984; 34: 939-944
        • Mendez M.F
        • Mastri A.R
        • Sung J.H
        • et al.
        Clinically diagnosed Alzheimer disease.
        Alzheimer Dis Assoc Disord. 1992; 6: 35-43
        • Menzel H.-J
        • Utermann G
        Apolipoprotein E phenotyping from serum by Western blotting.
        Electrophoresis. 1986; 7: 492-495
        • Mori H
        • Hosoda K
        • Matsubara E
        • et al.
        Tau in cerebrospinal fluids.
        Neurosci Lett. 1995; 186: 181-183
        • Motter R
        • Vigo-Pelfrey C
        • Kholodenko D
        • et al.
        Reduction of β-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease.
        Ann Neurol. 1995; 38: 643-648
        • Munroe W.A
        • Southwick P.C
        • Chang L
        • et al.
        Tau protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer’s disease.
        Ann Clin Lab Sci. 1995; 25: 207-217
        • Parnetti L
        • Palumbo B
        • Cardinali L
        • et al.
        Cerebrospinal fluid neuron-specific enolase in Alzheimer’s disease and vascular dementia.
        Neurosci Lett. 1995; 183: 43-45
        • Pizzi M
        • Valerio A
        • Arrighi V
        • et al.
        Antisense strategy unravels tau proteins as molecular risk factors for glutamate-induced neurodegeneration.
        Cell Mol Neurobiol. 1994; 14: 569-578
        • Pizzi M
        • Valerio A
        • Arrighi V
        • et al.
        Inhibition of glutamate-induced neurotoxicity by a tau antisense oligonucleotide in primary culture of rat cerebellar granule cells.
        Eur J Neurosci. 1995; 7: 1603-1613
        • Reisberg B
        • Ferris S.H
        • DeLeon M.J
        • et al.
        The Global Deterioration Scale for Assessment of Primary Degenerative Dementia.
        Am J Psychiatry. 1982; 139: 1136-1139
        • Riemenschneider M
        • Buch K
        • Schmolke M
        • Kurz A
        • Guder W.G
        Cerebrospinal protein tau is elevated in early Alzheimer’s disease.
        Neurosci. Lett. 1996; 212: 209-211
        • Samuel W
        • Terry R.D
        • Maslich E
        Frontal cortex and nucleus basalis pathology in Alzheimer’s disease.
        Arch Neurol. 1994; 51: 772-778
        • Skoog I
        • Vanmechelen E
        • Andreasson L.A
        • et al.
        A population-based study of tau protein and ubiquitin in cerebrospinal fluid in 85-year-olds.
        Neurosci Lett. 1996; 214: 163-166
        • Strittmatter W.J
        • Saunders A.M
        • Schmechel D
        • et al.
        Apolipoprotein E.
        Proc Natl Acad Sci USA. 1993; 90: 1977-1981
        • Tapiola T
        • Overmyer M
        • Lehtovirta M
        • et al.
        The level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimer’s disease.
        Neuroreport. 1997; 8: 3961-3963
        • Tato R.E
        • Frank A
        • Hernanz A
        Tau protein concentrations in cerebrospinal fluid of patients with dementia of the Alzheimer type.
        J Neurol Neurosurg Psychiatry. 1995; 59: 280-283
        • Terry R.D
        Neuropathological changes in Alzheimer disease.
        in: Svennerholm L Asbury A.K Reisfeld R.A Progress in Brain Research. Elsevier, Amsterdam1994: 303-390
        • Terry R.D
        • Hansen L.A
        • DeTeresa R
        • et al.
        Senile dementia of the Alzheimer type without neocortical neurofibrillarly tangles.
        J Neuropathol Exp Neurol. 1987; 46: 2262-2268
        • Vandermeeren M
        • Mercken M
        • Vanmechelen E
        • et al.
        Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay.
        J Neurochem. 1993; 61: 1828-1834
        • Victoroff J
        • Mack W.J
        • Lyness S.A
        • et al.
        Multicenter clinicopathological correlation in dementia.
        Am J Psychiatry. 1995; 152: 1476-1484
        • Vigo-Pelfrey C
        • Seubert P
        • Barbour R
        • et al.
        Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer’s disease.
        Neurology. 1995; 45: 788-793
        • Wolozin B
        • Davies P
        Alzheimer-related neuronal protein A68.
        Ann Neurol. 1987; 22: 521-526