Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease.

OBJECTIVES To study the diagnostic potential of the 42 amino acid form of beta-amyloid (beta-amyloid(1-42)) in cerebrospinal fluid (CSF) as a biochemical marker for Alzheimer disease (AD), the intra-individual biological variation of CSF-beta-amyloid(1-42) level in patients with AD, and the possible effects of differential binding between beta-amyloid and apolipoprotein E isoforms on CSF-beta-amyloid(1-42) levels. DESIGN A 20-month prospective follow-up study. SETTING Community population-based sample of consecutive patients with AD referred to the Piteå River Valley Hospital, Piteå, Sweden. PATIENTS Fifty-three patients with AD (mean +/- SD age, 71.4 +/- 7.4 years) diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria and 21 healthy, age-matched (mean +/- SD age, 68.8 +/- 8.0 years) control subjects. MAIN OUTCOME MEASURES Cerebrospinal fluid beta-amyloid(1-42) level--analyzed using enzyme-linked immunosorbent assay--and severity of dementia--analyzed using the Mini-Mental State Examination. RESULTS Mean +/- SD levels of CSF-beta-amyloid(1-42) were decreased (P<.001) in patients with AD (709 +/- 304 pg/mL) compared with controls (1678 +/- 436 pg/mL). Most patients with AD (49 [92%] of 53 patients) had reduced levels (<1130 pg/mL). A highly significant correlation (r = 0.90; P<.001) between baseline and 1-year follow-up CSF-beta-amyloid(1-42) levels was found. There were no significant correlations between CSF-beta-amyloid(1-42) level and duration (r = -0.16) or severity (r = -0.02) of dementia. Low levels were also found in patients with mild dementia (Mini-Mental State Examination score, >25). CONCLUSIONS The sensitivity of CSF-beta-amyloid(1-42) level as a diagnostic marker for AD is high. The intra-individual biological variation in CSF-beta-amyloid(1-42) level is low. Low CSF-beta-amyloid(1-42) levels are also found in the earlier stages of dementia in patients with AD. These findings suggest that CSF-beta-amyloid(1-42) analyses may be of value in the clinical diagnosis of AD, especially in the early course of the disease, when drug therapy may have the greatest potential of being effective but clinical diagnosis is particularly difficult.

[1]  C. Vigo‐Pelfrey,et al.  Characterization of beta-amyloid peptide from human cerebrospinal fluid. , 1993, Journal of neurochemistry.

[2]  N. Suzuki,et al.  Biochemical evidence for the long-tail form (Aβ1-42/43) of amyloid β protein as a seed molecule in cerebral deposits of alzheimer′s disease , 1994 .

[3]  K. Blennow,et al.  Clinical Heterogeneity of Probable Alzheimer's Disease , 1992, Journal of geriatric psychiatry and neurology.

[4]  A. Delacourte,et al.  Quantitation of Alzheimer's amyloid peptide and identification of related amyloid proteins by dot-blot immunoassay , 1995, Brain Research.

[5]  G. Getz,et al.  Isoform-specific binding of apolipoprotein E to beta-amyloid. , 1994, The Journal of biological chemistry.

[6]  A. Wallin,et al.  Low frequency of post‐lumbar puncture headache in demented patients , 1993, Acta neurologica Scandinavica.

[7]  K. Blennow,et al.  Neurochemical Dissection of Synaptic Pathology in Alzheimer's Disease , 1998, International Psychogeriatrics.

[8]  P. Yates,et al.  ALZHEIMER'S PRESENILE DEMENTIA, SENILE DEMENTIA OF ALZHEIMER TYPE AND DOWN'S SYNDROME IN MIDDLE AGE FORM AN AGE RELATED CONTINUUM OF PATHOLOGICAL CHANGES , 1984, Neuropathology and applied neurobiology.

[9]  M. Ball,et al.  Morphological and Biochemical Analyses of Amyloid Plaque Core Proteins Purified from Alzheimer Disease Brain Tissue , 1993, Journal of neurochemistry.

[10]  S. Younkin,et al.  Amyloid beta protein (A beta) in Alzheimer's disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). , 1995, The Journal of biological chemistry.

[11]  P. Lansbury,et al.  The C‐Terminus of the β Protein is Critical in Amyloidogenesis a , 1993 .

[12]  P. Scheltens,et al.  Neuro-imaging in the diagnosis of Alzheimer's disease I. Computer tomography and magnetic resonance imaging , 1992, Clinical Neurology and Neurosurgery.

[13]  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.

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

[15]  K. Grzeschik,et al.  The precursor of Alzheimer??s disease amyloid A4 protein resembles a cell-surface receptor , 1987 .

[16]  S. Younkin,et al.  Amyloid β protein levels in cerebrospinal fluid are elevated in early‐onset Alzheimer's disease , 1994 .

[17]  P. Southwick,et al.  Assessment of Amyloid β Protein in Cerebrospinal Fluid as an Aid in the Diagnosis of Alzheimer's Disease , 1996 .

[18]  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.

[19]  P. Lansbury,et al.  The C-terminus of the beta protein is critical in amyloidogenesis. , 1993, Annals of the New York Academy of Sciences.

[20]  R. Martins,et al.  A4 amyloid protein deposition and the diagnosis of Alzheimer's disease , 1988, Neurology.

[21]  D. Selkoe,et al.  Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids , 1992, Nature.

[22]  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.

[23]  M. Leon,et al.  Leukoencephalopathy in normal and pathologic aging: 2. MRI of brain lucencies. , 1986, AJNR. American journal of neuroradiology.

[24]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[25]  M. Roth,et al.  Cortical neuronal counts in normal elderly controls and demented patients , 1983, Neurobiology of Aging.

[26]  David M. A. Mann,et al.  The neuropathology of Alzheimer's disease: A review with pathogenetic, aetiological and therapeutic considerations , 1985, Mechanisms of Ageing and Development.

[27]  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.

[28]  R. DeTeresa,et al.  Neocortical morphometry, lesion counts, and choline acetyltransferase levels in the age spectrum of Alzheimer's disease , 1988, Neurology.

[29]  T. Erkinjuntti,et al.  CT in the differential diagnosis between Alzheimer's disease and vascular dementia , 1987, Acta neurologica Scandinavica.

[30]  P. Scheltens,et al.  White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer's disease. Evidence for heterogeneity. , 1992, Brain : a journal of neurology.

[31]  J. Tomazewska.  [Department of rehabilitation]. , 1976, Pielegniarka i polozna.

[32]  M. Roth,et al.  The association of clinical and neurological findings and its bearing on the classification and aetiology of Alzheimer's disease. , 1986, British medical bulletin.

[33]  C. Masters,et al.  AMYLOID PLAQUE CORE PROTEIN IN ALZHEIMERʼS DISEASE AND AGED DOWNʼS SYNDROME , 1985 .

[34]  D. Selkoe,et al.  Amyloid β-peptide is produced by cultured cells during normal metabolism , 1992, Nature.

[35]  M. Tabaton,et al.  Soluble amyloid beta-protein is a marker of Alzheimer amyloid in brain but not in cerebrospinal fluid. , 1994, Biochemical and biophysical research communications.

[36]  T. Iwatsubo,et al.  High tissue content of soluble beta 1-40 is linked to cerebral amyloid angiopathy. , 1994, The American journal of pathology.

[37]  K. Blennow,et al.  White‐matter lesions on CT in Alzheimer patients: relation to clinical symptomatology and vascular factors , 1991, Acta neurologica Scandinavica.

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

[39]  C. Vigo‐Pelfrey,et al.  Rapid Communication: Characterization of β‐Amyloid Peptide from Human Cerebrospinal Fluid , 1993 .

[40]  H. E. Solberg.  Approved recommendation (1987) on the theory of reference values. Part 5. Statistical treatment of collected reference values. Determination of reference limits , 1987 .

[41]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[42]  A D Roses,et al.  Apolipoprotein E alleles as risk factors in Alzheimer's disease. , 1996, Annual review of medicine.

[43]  S. Harik.  Cerebrospinal Fluid in Diseases of the Nervous System, 2nd Ed. , 1994, Neurology.

[44]  Weiming Xia,et al.  Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice , 1997, Nature Medicine.

[45]  G. Glenner,et al.  Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein , 1984 .

[46]  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.

[47]  Hans Förstl,et al.  Analysis of Heterogeneous βA4 Peptides in Human Cerebrospinal Fluid and Blood by a Newly Developed Sensitive Western Blot Assay* , 1996, The Journal of Biological Chemistry.

[48]  D. Rothschild,et al.  PATHOLOGIC CHANGES IN SENILE PSYCHOSES AND THEIR PSYCHOBIOLOGIC SIGNIFICANCE , 1937 .

[49]  T. Iwatsubo,et al.  Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: Evidence that an initially deposited species is Aβ42(43) , 1994, Neuron.

[50]  S. Hirai,et al.  Amyloid β protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease , 1997, Journal of the Neurological Sciences.

[51]  R. Griggs.  Cerebrospinal Fluid in Diseases of the Nervous System , 1981, Neurology.

[52]  R. Motter,et al.  Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease , 1997 .

[53]  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.

[54]  S. Estus,et al.  Production of the Alzheimer amyloid beta protein by normal proteolytic processing. , 1992, Science.

[55]  M. Ball,et al.  Water-soluble A(N-40, N-42) Oligomers in Normal and Alzheimer Disease Brains (*) , 1996, The Journal of Biological Chemistry.

[56]  G. Glenner,et al.  Differences Between Vascular and Plaque Core Amyloid in Alzheimer's Disease , 1988, Journal of neurochemistry.

[57]  J. Anderson,et al.  AGE‐RELATED VARIATIONS IN THE NEURON CONTENT OF THE CEREBRAL CORTEX IN SENILE DEMENTIA OF ALZHEIMER TYPE , 1985, Neuropathology and applied neurobiology.

[58]  T. Iwatsubo,et al.  Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). , 1994, Neuron.

[59]  K. Blennow,et al.  White matter low attenuation on computed tomography in Alzheimer's disease and vascular dementia – diagnostic and pathogenetic aspects , 1989, Acta neurologica Scandinavica.

[60]  Khadija Iqbal,et al.  Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer's disease. , 1993, Archives of biochemistry and biophysics.