The levels of cerebrospinal fluid Aβ40 and Aβ42(43) are regulated age-dependently

Decreased levels of cerebrospinal fluid (CSF) Abeta42 is a diagnostic marker of Alzheimer's disease. To clarify the biological basis of this marker, the physiological alterations of CSF Abeta40 and Abeta42 by aging were studied. CSF samples from 92 normal subjects between 8 and 89 years old were measured using a specific ELISA for Abeta40 and Abeta42(43). High concentrations of Abeta40 and Abeta42(43) in the young group, under 29 years old, changed to be at low concentrations in the adult group between 30 and 59 years old. Subsequently, the levels increased again with age. Third order regression analysis showed a significant correlation between the levels of Abeta40 and age (Y = - 169 X(3) + 3.1X(2)- 0.02X + 4135; P < 0.034) and between the levels of Abeta42(43) and age (Y = - 46 X(3) + 0.9 X(2)- 0.005X + 992; P < 0.005). The levels of CSF Abeta40 and Abeta42(43) were physiologically regulated to show a U-shaped natural course in normal aging. These findings suggested that the physiological increase of Abeta42(43) over 59 years of age is selectively inhibited in Alzheimer's disease.

[1]  D. Selkoe,et al.  Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production , 1992, Nature.

[2]  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.

[3]  J. Kaye,et al.  High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. , 1998, Archives of neurology.

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

[5]  E. Matsubara,et al.  Lipoprotein‐free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer's disease and Down's syndrome , 1999, Annals of neurology.

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

[7]  S. Tsuji,et al.  The beta APP717 Alzheimer mutation increases the percentage of plasma amyloid-beta protein ending at A beta 42(43) , 1997, Neurology.

[8]  S. Hirai,et al.  Combination assay of CSF Tau, Aβ1-40 and Aβ1-42(43) as a biochemical marker of Alzheimer's disease , 1998, Journal of the Neurological Sciences.

[9]  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.

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

[11]  B Engvall,et al.  Cerebrospinal fluid Aβ42 is increased early in sporadic Alzheimer's disease and declines with disease progression , 1999, Annals of neurology.

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

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

[14]  S. Younkin,et al.  An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. , 1994, Science.

[15]  J. Hardy,et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 , 1996, Nature.

[16]  P. Deyn,et al.  Improved discrimination of AD patients using β-amyloid(1-42) and tau levels in CSF , 1999, Neurology.

[17]  E. Matsubara,et al.  Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease , 1999, Neuroscience Letters.

[18]  S. Hirai,et al.  Longitudinal study of cerebrospinal fluid levels of tau, Aβ1–40, and Aβ1–42(43) in Alzheimer's disease: A study in Japan , 1998 .

[19]  H. Wiśniewski,et al.  Plasma amyloid β‐peptide 1–42 and incipient Alzheimer's disease , 1999 .

[20]  D. Schenk,et al.  Concentrations of amyloid-β protein in cerebrospinal fluid increase with age in patients free from neurodegenerative disease , 1994, Neuroscience Letters.

[21]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[22]  K. Blennow,et al.  Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. , 1999, Archives of neurology.

[23]  T. Tokuda,et al.  Plasma Levels of amyloid β proteins Aβ1–40 and Aβ1–42(43) are elevated in Down's syndrome , 1997 .

[24]  A. Burns.  Clinical diagnosis of Alzheimer's disease , 1991 .

[25]  P. Mehta,et al.  Traumatic Brain Injury Increases β‐Amyloid Peptide 1‐42 in Cerebrospinal Fluid , 1998 .

[26]  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.

[27]  B. Winblad,et al.  Amyloid β-peptide in cerebrospinal fluid in individuals with the Swedish Alzheimer amyloid precursor protein mutation , 1995, Neuroscience Letters.

[28]  H. Wiśniewski,et al.  Soluble amyloid β-protein in the cerebrospinal fluid from patients with Alzheimer's disease, vascular dementia and controls , 1994, Journal of the Neurological Sciences.

[29]  K Namekata,et al.  Quantitation of amyloid beta-protein (A beta) in the cortex during aging and in Alzheimer's disease. , 1998, The American journal of pathology.

[30]  K. Davis,et al.  CSF beta-amyloid, cognition, and APOE genotype in Alzheimer’s disease , 1999, Neurology.

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