 |
|
Plasma and Cerebrospinal Fluid Levels of Amyloid  Proteins 1-40 and 1-42 in Alzheimer Disease
Pankaj D. Mehta, PhD;
Tuula Pirttilä, MD, PhD;
Sangita P. Mehta, MS;
Eugene A. Sersen, PhD;
Paul S. Aisen, MD;
Henryk M. Wisniewski, MD, PhD
Arch Neurol. 2000;57:100-105.
ABSTRACT
Background In brains with AD, A is a major component of diffuse plaques. Previous reports showed that CSF A42 levels were lower in patients with AD than in controls. Although studies showed higher plasma A42 levels in familial AD, a recent report has indicated that plasma A42 levels were similar in a sporadic AD group and controls. However, no information is published on plasma A40 and A42 levels in relation to Apo E genotype or severity of dementia in sporadic AD.
Objective To examine plasma and cerebrospinal fluid (CSF) levels of amyloid protein 1-40 (A40) and 1-42 (A42) levels in patients with probable Alzheimer disease (AD) and elderly nondemented control subjects in relation to the apolipoprotein E (Apo E) genotype and dementia severity.
Setting Two university medical centers.
Patients and Methods Levels of A40 and A42 were measured in plasma from 78 patients with AD and 61 controls and in CSF from 36 patients with AD and 29 controls by means of a sandwich enzyme-linked immunosorbent assay.
Results Mean plasma A40 levels were higher in the AD group than in controls (P = .005), but there was substantial overlap; A42 levels were similar between the groups. Levels of A40 and A42 showed no association with sex or Mini-Mental State Examination scores. There was a significant relationship between age and A40 level in controls but not in the AD group. Levels of A40 were higher in patients with AD with the Apo E  4 allele than in controls (P<.01). Cerebrospinal fluid A40 levels were similar in the AD group and controls. However, A42 levels were lower in the AD group than in controls (P<.001). The levels showed no association with severity of dementia.
Conclusions Although mean plasma A40 levels are elevated in sporadic AD and influenced by Apo E genotype, measurement of plasma A40 levels is not useful to support the clinical diagnosis of AD. Lower levels of CSF A42 in the AD group are consistent with previous studies.
INTRODUCTION
NEUROFIBRILLARY tangles and amyloid-bearing neuritic plaques in the limbic and cerebral cortices are the characteristic neuropathologic lesions in brains with Alzheimer disease (AD).1-2 The major component of neuritic plaques is the amyloid protein (A), a small 39-42 amino acid residue protein derived through proteolytic processing of a larger membrane-bound glycoprotein, the amyloid –precursor protein (APP).3 Secreted, soluble A is a product of normal cell metabolism and found in various body fluids, including plasma and cerebrospinal fluid (CSF).4-5 Recent studies have shown that in brains with AD, A ending at residue 42 (A42) is deposited first and constitutes the predominant form in senile plaques; whereas A ending at residue 40 (A40) is deposited later in the disease and is prominent in vascular amyloid deposits.6-8 Accumulating data support the central role of A42 in the formation of neuritic plaques.
To develop a laboratory test to support the diagnosis of probable AD, investigators have examined levels of A40 and A42 in CSF of patients with AD and control subjects.9-12 The data showed that CSF A42 levels were lower in patients with AD than in controls. However, there was a significant overlap between the groups. Although recent studies have recommended measurements of CSF A42 and microtubule-associated protein tau concentrations in supporting the diagnosis of AD, this assay is not used widely because it requires lumbar puncture.
Recently, 2 studies measured plasma A40 and A42 levels in patients with AD.13-14 One study13 showed that plasma A40 and A42 levels were 2- to 3-fold higher in patients with familial AD and with APP and presenilin 1 and 2 mutations compared with patients with sporadic AD and controls. The second study14 showed no significant differences in plasma A40 and A42 levels between patients with AD and controls. However, none of these studies examined the relationship between plasma A40 and A42 levels and age, sex, or Mini-Mental State Examination (MMSE) score.
Apolipoprotein E (Apo E) is a 34-kd polymorphic protein that is involved in the transportation and redistribution of lipids among various tissues. The Apo E 4 allele is a significant risk factor for the development of sporadic and familial late-onset AD.15-16 Although studies17-18 have shown an association of Apo E 4 alleles with increased amyloid deposition in brains with AD, none examined the relationship between plasma A40 and A42 levels and the Apo E genotype.
Herein, we report the quantitation of plasma and CSF A40 and A42 levels in patients with probable AD and elderly nondemented controls and analyze the relationships with age, sex, MMSE score, and Apo E genotype.
SUBJECTS AND METHODS
SUBJECTS
The study included 42 patients with sporadic AD and 46 elderly, nondemented controls from the Alzheimer Disease Research Center, Mount Sinai Medical Center, New York, NY, and 36 patients with probable AD and 29 controls from the Department of Neurology, Tampere University Medical Center, Tampere, Finland. Informed consent was obtained from all participants or their guardians. The diagnosis of probable AD was made according to the criteria of the National Institute of Neurological Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.19 Age, sex, Apo E genotype, and MMSE scores of the AD group and controls are given in Table 1. The median duration of disease in the AD group was 3 years (range, 0.5-10 years).
|
|
|
|
Table 1. Demographic Characteristics of Patients With AD and Controls*
|
|
|
PLASMA AND CSF COLLECTION
Blood was collected from both centers between 10 AM and 2 PM in tubes containing sodium ethylenediaminetetraacetic acid. After 15 minutes, plasma samples were centrifuged at 3000 rpm at 4°C. Supernatants were collected, divided into aliquots, and frozen at -80°C. Plasma samples were collected from 78 patients with AD and 61 controls.
Cerebrospinal fluid samples were collected from all subjects recruited from the Tampere center. The controls included patients with headache (n = 16) and mild depression (n = 13). Samples were obtained at the time of diagnostic lumbar puncture, divided into aliquots, and stored frozen at -80°C until further study. All CSF samples were tested for cell counts and levels of glucose and total protein. Samples contaminated with blood were excluded.
APO E GENOTYPING
Apolipoprotein E genotypes of blood samples from the AD and control groups were determined using polymerase chain reaction methods as previously described.20 The polymerase chain reaction products were digested with HhaI subjected to polyacrylamide gel electrophoresis, and separated DNA fragments were visualized using ethidium bromide staining.
ANTISERUM SAMPLES
We conjugated A32-40 and A33-42 peptides synthesized commercially (Ana Spec, San Jose, Calif) to keyhole-limpet hemocyanin in phosphate-buffered saline solution (PBS) with 0.5% glutaraldehyde. Rabbits were immunized with the peptides, and the specificity of antiserum samples R162 produced against A40 and R164 raised against A42 was examined using a sandwich enzyme-linked immunosorbent assay (ELISA). There was a strong response of R162 with 1 ng/mL of A40 but no detectable response with 10 ng/mL of A42. Similarly, R164 was found to be specific to A42 but showed no reactivity to A40. Western blot analysis also showed that R162 was specific to A40 and that R164 was specific to A42 as described previously.21
A40 AND A42 ELISA
Levels of A were measured using monoclonal antibody 6E10 (specific to an epitope present on 1-16 amino acid residues of A), rabbit antiserum R162 (specific to a peptide corresponding to A40), and rabbit antiserum 164 (specific to a peptide corresponding to A42) in a double-antibody sandwich ELISA as described previously.22 Briefly, 100 µL of monoclonal antibody 6E10 (2.5 µg/mL) diluted in carbonate-bicarbonate buffer (pH 9.6) was coated in wells of microtiter plates and incubated at 4°C overnight. After washing the plates with PBS containing 0.05% polyoxyethylene sorbitan monolaurate (Tween 20; Sigma-Aldrich Corp, St Louis, Mo) (PBST), wells were blocked for an hour with 200 µL of 10% normal sheep serum in PBS to avoid nonspecific binding. Plates were washed again, and 100 µL of standards (A40 and A42; Bachem, Torrance, Calif) diluted in PBST with 0.5% bovine serum albumin or plasma (undiluted) were applied and incubated 2 hours at room temperature and 4°C overnight. After washing, the plates were incubated with biotinylated rabbit antiserum samples 162 or 164 diluted in PBST with 0.5% bovine serum albumin at room temperature for 1 hour 15 minutes. After washing, NeutrAvidin–horseradish peroxidase conjugated (Pierce, Rockford, Ill) diluted in PBST was added into the wells, and plates were incubated 1 hour at room temperature. Plates were washed again, and 100 µL of o-phenylenediamine dihydrochloride (Sigma-Aldrich Corp) in 50-mmol/L citric acid and 100-mmol/L sodium phosphate buffer (pH 5.0) was added in each well. The reaction was stopped by adding 100 µL of 1N sulfuric acid. The optical density (OD) was measured at 490 nm in a micro-ELISA reader. The relationship between OD and the A40 and A42 concentrations was determined using a 4-feature logistic logarithm function. Nonlinear curve fitting was performed with a commercially available program (KinetiCalc; Biotek Instruments, Inc, Winooski, Vt) to convert OD of plasma to estimated concentrations. All samples were coded; investigators were unaware of group assignment (AD vs control group) until levels were measured and recorded.
ASSAY SENSITIVITY AND PRECISION
Detection limit of the assay was 20 pg/mL for A40 and 40 pg/mL for A42. The percentage coefficients of variation ranged from 8% to 14% (interassay) and 10% to 18% (intra-assay). When A40 and A42 levels in CSF and plasma from 20 patients with AD were quantitated using a second set of antiserum samples specific for A40 (R163) and A42 (R165) and compared with the levels quantitated using R162 and R164, there was a significant correlation for A40 (r = 0.83; P<.001) and for A42 (r = 0.71; P = .005).
STATISTICAL ANALYSIS
The groups were compared for each constituent, using the Kruskal-Wallis 1-way analysis of variance with a Bonferroni correction for multiple comparisons. Pearson correlation with Bonferroni correction was used to analyze the relationship between the variables. Pairs of groups were compared using the Mann-Whitney test. The level of P<.01 was considered significant.
RESULTS
Table 1 shows the demographic characteristics of plasma samples from the AD and control groups. The groups did not differ significantly (P = .79) by age or sex. The Apo E 4 allele frequencies were 52 (67%) of 78 in the AD group and 13 (21%) of 61 in the control group. The higher frequency of Apo E 4 allele reported in the AD group was consistent with previous findings in Finland.23-24 The frequency of Apo E 4 allele in controls was similar to that reported previously.15-16
PLASMA LEVELS
Levels of A40 were higher in the AD group than in controls (P = .005) (Figure 1). The levels were higher in patients with AD and the Apo E 4 allele than in those without the allele, but with the borderline significance (P = .03) (Table 2). However, the levels were higher than those in controls with and without the Apo E 4 allele (P = .01). Levels of A42 were similar between patients with AD and controls; they were also similar in both groups with and without Apo E 4 allele.
There was a significant association between A40 and A42 levels for patients with AD (r = 0.38; P = .008). However, a similar relationship reached borderline significance in controls (r = 0.31; P = .03). There was a significant relationship between age and A40 levels in controls (r = 0.37; P = .008), but not in patients with AD (r = 0.27; P = .07). However, there was no significant relationship between age and A42 level in patients with AD or controls. There were no significant differences in A40 and A42 levels in men compared with women. There was no significant association between MMSE scores and levels of A40 and A42 in patients with AD or controls. The MMSE scores did not differ significantly between patients with AD with the Apo E 4 allele and those without the allele.
CSF LEVELS
Levels of A40 in CSF were similar in patients with AD and controls. However, A42 levels were lower in patients with AD than in controls (P<.001) (Figure 2). The levels were lower in patients with AD with the Apo E 4 allele than in controls without the allele (P = .004) (Table 3). There was no significant difference in A42 levels between patients with AD with the Apo E 4 allele and controls with the allele. The levels showed no association with age or sex in either group. There was also no relation between the levels and MMSE scores in patients with AD and controls.
COMMENT
Unlike earlier studies,13-14 our results showed that mean plasma A40 levels were elevated in patients with AD, compared with controls. Because there was a considerable overlap between both groups, measurement of plasma A40 levels is not useful as a diagnostic tool to distinguish patients with sporadic AD from elderly, nondemented controls. The finding that plasma A42 levels are similar between patients with AD and controls is consistent with those recently reported.13-14 Discrepancies between our results and those reported by others13-14 may result from differences in patient populations. Our data suggest that Apo E genotype influences A40 levels; the frequency of Apo E 4 allele was not reported in the earlier studies. Also, different ELISA methods and specificity of antibodies likely influence the data. However, these factors are not likely responsible for the differences seen in plasma A40 levels between patients with AD and controls, since our data on CSF A40 and A42 levels are consistent with a number of published data.9-12
There are various difficulties in the measurement of A levels in body fluids. Low concentrations of A in plasma necessitate a sensitive and reliable laboratory quantitation assay. Also, A binds to carrier proteins such as Apo E and Apo J that are present in plasma.25-26 Antibody epitopes of A may be masked by such binding and interfere with detection of true A values in body fluids using sandwich ELISA. Investigators have also reported cross-reactivities between A and several plasma proteins, including immunoglobulin G27 and fibrinogen.28 However, our immunoblotting studies did not show staining of additional bands with specific antibodies to A40 and A42.29 The monoclonal antibody 6E10 recognizes APP and A in CSF and plasma. However, APP did not cause any interference in our assay as confirmed by the recovery data of A in CSF as described previously.29
The significance of plasma A levels in relation to A accumulation in the brain is unclear. If plasma A originates from tissues other than brain, there may not be an association between plasma A levels and A deposited in the brain. However, investigators have shown that A–Apo E and A–Apo J complexes cross the blood-brain barrier26; thus, A present in plasma may contribute to the development of A deposits in the brain. Previous studies showed that A levels varied highly in brains of patients with AD, and those with massive amyloid deposition contained predominantly A40.7, 30 In some patients with sporadic AD, high plasma levels of A40 may contribute to the accumulation of A40 in preexisting plaques.
Age and Apo E genotype are major risk factors for sporadic AD. We found a significant relationship between age and plasma A40 levels in controls and between A40 and Apo E genotype in patients with AD. These results are interesting, since investigators have suggested that higher plasma A40 or A42 levels may play a part in 10% to 20% of sporadic AD before the onset of clinical symptoms.13 Although our findings showed increased plasma A40 levels in AD with the Apo E 4 allele, we do not know whether the levels were present several years before the onset of probable AD. Further longitudinal measurements are needed in individuals with mild cognitive symptoms or asymptomatic first-degree relatives of patients with AD in diagnosing early AD.
Although we found no relationship between severity of dementia and A levels in the cross-sectional sample, longitudinal studies will be necessary to determine conclusively whether there is a relationship between plasma A and progression of AD. Such studies are particularly important to determine whether modulation of plasma A may be a useful measure of disease-modifying therapies.
Our CSF results showing lower mean A42 levels in AD are consistent with those of previous reports.9-12 The absence of correlation with age or sex is in agreement with earlier reports. Our studies showed no significant relationship between these levels and MMSE scores, consistent with the data of Motter et al9 and Tamaoka et al10; others showed weak12 or strong31 correlation between the levels and dementia severity. The reason for the discrepancy may be that in our study, the sample size was small, and most patients with AD were mildly demented. However, our results are consistent with the histopathological data, which showed no correlation between number of plaques and A deposition in the brain.32-34 Further studies with a greater number of samples are essential to clarify these controversial findings.
Our findings that CSF A42 levels were lower in patients with AD with the Apo E 4 allele than in patients without the allele agree with those of a number of published reports. However, our studies showed no significant differences in CSF A42 levels between patients with AD with the Apo E 4 allele and controls with the allele. The findings are different fromthose reported by Galasko et al12 and Hulstaert et al,35 who reported significant differences. The reason for this discrepancy may be that in our studies, the number of controls with the Apo E 4 is smaller than in the latter studies.12, 35
The values of CSF A40 and A42 differed between research laboratories. For example, we found mean CSF A42 levels in AD were 35 pg/mL, in contrast to the range seen from 125 fmol/mL to 833 pg/mL in previous studies.9-12 Conflicting findings may result from differences in the affinity of specific A antiserum samples and the purity and solubilization of peptides used as standards. In addition to the differences in the ELISA methods, conflicting data could result from differences in sample collection and storage conditions. It has been reported that A values decreased over time, even if the CSF samples were frozen.36 Repeated freezing and thawing of CSF could also result in the loss of A. Several studies have shown that A levels are lower in CSF collected in glass or polystyrene tubes than polypropylene tubes. Although our samples were divided into aliquots and well frozen in polypropylene tubes, storing samples frozen over a long time and other unknown factors might have influenced the true value of A in CSF.
In summary, although blood is easy to obtain, it is still unclear if there are systemic changes specific for AD, and to what extent changes in blood composition reflect pathologic changes seen in the brain. Cerebrospinal fluid may better represent brain abnormalities than blood, but drawing of CSF is an invasive procedure. Further measurements of A40 and A42 levels in matched plasma, CSF, and autopsy brain tissues and correlation with dementia severity and Apo E genotype are needed to increase our understanding of the significance of plasma and CSF measurements.
AUTHOR INFORMATION
Accepted for publication June 2, 1999.
The work was supported by funds provided by New York State through its Office of Mental Retardation and Developmental Disabilities, Albany.
Reprints: Pankaj D. Mehta, PhD, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd, Staten Island, NY 10314 (e-mail: pdmehta{at}worldnet.att.net).
From the Departments of Immunology (Dr Mehta and Ms Mehta), Psychology (Dr Sersen), and Neuropathology (Dr Wisniewski), New York State Institute for Basic Research in Developmental Disabilities, Staten Island, and the Department of Psychiatry, Mount Sinai School of Medicine, New York (Dr Aisen), NY; and the Department of Neurology, Tampere University Hospital, Tampere, Finland (Dr Pirttilä). Dr Aisen is now with the Department of Neurology, Georgetown University Medical Center, Washington, DC.
REFERENCES
1. Wisniewski HM, Wegiel J. The neuropathology of Alzheimer's disease. Neuroimaging Clin N Am. 1995;5:45-57.
PUBMED
2. Selkoe DJ. Alzheimer's disease: a central role for amyloid. J Neuropathol Exp Neurol. 1994;53:438-447.
WEB OF SCIENCE
| PUBMED
3. Selkoe D. Normal and abnormal biology of the -amyloid precursor protein. Annu Rev Neurosci. 1994;17:489-517.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
4. Mehta PD, Kim KS, Wisniewski HM. ELISA as a laboratory test to aid the diagnosis of Alzheimer's disease. Techniques Diagn Pathol. 1991;2:99-112.
5. Hass C, Scholossmacher MG, Hung A-Y, et al. Amyloid -peptide is produced by cultured cells during normal metabolism. Nature. 1992;359:322-326.
FULL TEXT
| PUBMED
6. Gravina SA, Libin H, Eckman CB, et al. Amyloid protein (A) in Alzheimer's disease brain: biochemical and immunocytochemical analysis with antibodies specific for forms of A40 and A42(43). J Biol Chem. 1995;270:7013-7016.
FREE FULL TEXT
7. Iwatsubo T, Odaka A, Suzuki N, et al. Visualization of A42/43 and A40 in senile plaques with end-specific A monoclonals: evidence that an initially deposited species is A42/43. Neuron. 1994;13:45-53.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
8. Younkin SG. Evidence that A42 is the real culprit in Alzheimer's disease. Ann Neurol. 1995;37:287-288.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
9. Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of -amyloid peptide 42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. 1995;38:643-648.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
10. Tamaoka A, Sawamura N, Fukushima T, et al. Amyloid protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease. J Neurol Sci. 1997;148:41-45.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
11. Shoji M, Matsubara E, Kanai M, et al. Combination assay of CSF Tau, A1-40 and A-42 (43) as a biochemical marker of Alzheimer's disease. J Neurol Sci. 1998;158:134-140.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
12. Galasko D, Chang L, Motter R, et al. High cerebrospinal fluid tau and low amyloid 42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol. 1998;55:937-945.
FREE FULL TEXT
13. Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid -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. Nat Med. 1996;2:864-870.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
14. Tamaoka A, Fukushima T, Sawamura N, et al. Amyloid protein in plasma from patients with sporadic Alzheimer's disease. J Neurol Sci. 1996;151:65-68.
15. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921-923.
FREE FULL TEXT
16. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of appolipoprotein E allele 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;43:1467-1472.
FREE FULL TEXT
17. Schmechel DE, Saunders AM, Strittmatter WJ, et al. Increased amyloid -peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:9649-9653.
FREE FULL TEXT
18. Rebeck GW, Reiter JS, Strickland DK, Hyman BT. Apolipoprotein E in sporadic Alzheimer's disease: allele variation and receptor interactions. Neuron. 1993;11:575-580.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
19. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939-944.
FREE FULL TEXT
20. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545-548.
ABSTRACT
21. Potempska A, Mack K, Mehta PD, et al. Quantification of sub-femtomole amounts of Alzheimer amyloid peptides. Amyloid. 1999;6:14-21.
WEB OF SCIENCE
| PUBMED
22. Mehta PD, Dalton AJ, Mehta SP, et al. Increased plasma amyloid protein 1-42 levels in Down syndrome. Neurosci Lett. 1998;241:13-16.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
23. Lehtimäki T, Pirttilä T, Mehta PD, Wisniewski HM, Frey H, Nikkari T. 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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
24. Polvikoski T, Sulkava R, Haltia M, et al. Apolipoprotein E, dementia, and cortical deposition of -amyloid protein. N Engl J Med. 1995;333:1242-1247.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
25. Matsubara E, Frangione B, Ghiso J. Characterization of apolipoprotein J–Alzheimer's A interaction. J Biol Chem. 1995;270:7563-7567.
FREE FULL TEXT
26. Zlokovic BV. Cerebrovascular transport of Alzheimer's amyloid and apolipoproteins J and E: possible anti-amyloidogenic role of the blood-brain barrier. Life Sci. 1996;59:1483-1497.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
27. Stern RA, Trojanowski JQ, Lee VM-Y, et al. Antibodies to the -amyloid peptide cross-react with conformational epitopes in human fibrinogen subunits from peripheral blood. FEBS Lett. 1990;264:43-47.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
28. Pardridge WM, Vinters HV, Miller BL, Tourtellotte WW, Eisenberg JB, Yang J. High molecular weight Alzheimer's disease amyloid peptide immunoreactivity in human serum and CSF is an immunoglobulin G. Biochem Biophys Res Commun. 1987;145:241-248.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
29. Pirttilä T, Kim KS, Mehta PD, Frey H, Wisniewski HM. Soluble amyloid -protein in the cerebrospinal fluid from patients with Alzheimer's disease, vascular dementia and controls. J Neurol Sci. 1994;127:90-95.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
30. Ishii K, Tamaoka A, Mizusawa H, et al. A1-40 but not A1-42 levels in cortex correlate with apolipoprotein E 4 allele dosage in sporadic Alzheimer's disease. Brain Res. 1997;748:250-252.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
31. Samuels SC, Silverman JM, Marin DB, et al. CSF beta-amyloid, cognition, and ApoE genotype in Alzheimer's disease. Neurology. 1999;52:547-551.
FREE FULL TEXT
32. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992;42:631-639.
FREE FULL TEXT
33. Samuel W, Terry RD, DeTeresa R, Butters N, Masliah E. Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia. Arch Neurol. 1994;51:772-778.
FREE FULL TEXT
34. Tamaoka A, Sawamura N, Odaka A, et al. Amyloid protein 1-42/43 (A1-42/43) in cerebellar diffuse plaques: enzyme-linked immunosorbent assay and immunocytochemical study. Brain Res. 1995;679:151-156.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
35. Hulstaert F, Blenow K, Ivanoiu A, et al. Improved discrimination of AD patients using -amyloid (1-42) and tau levels in CSF. Neurology. 1999;52:1555-1562.
FREE FULL TEXT
36. Southwick PC, Yamagata S, Echols CL, et al. Assessment of amyloid protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer's disease. J Neurochem. 1996;66:259-265.
WEB OF SCIENCE
| PUBMED
 CiteULike  Connotea  Delicious  Digg  Facebook  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLE
Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 2000;57(1):142-143.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Plasma A{beta} and PET PiB binding are inversely related in mild cognitive impairment
Devanand et al.
Neurology 2011;77:125-131.
ABSTRACT
| FULL TEXT
Diet Intervention and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment
Bayer-Carter et al.
Arch Neurol 2011;68:743-752.
ABSTRACT
| FULL TEXT
Plasma {beta}-Amyloid and Cognitive Decline
Cosentino et al.
Arch Neurol 2010;67:1485-1490.
ABSTRACT
| FULL TEXT
Effect of Chronic hCG Administration on Alzheimer's-Related Cognition and A{beta} Accumulation in PS1KI Mice
Barron et al.
Endocrinology 2010;151:5380-5388.
ABSTRACT
| FULL TEXT
Plasma A{beta}42 and A{beta}40 as markers of cognitive change in follow-up: a prospective, longitudinal, population-based cohort study
Seppala et al.
J. Neurol. Neurosurg. Psychiatry 2010;81:1123-1127.
ABSTRACT
| FULL TEXT
Effects of Aerobic Exercise on Mild Cognitive Impairment: A Controlled Trial
Baker et al.
Arch Neurol 2010;67:71-79.
ABSTRACT
| FULL TEXT
Ovariectomy and 17{beta}-Estradiol Replacement Do Not Alter {beta}-Amyloid Levels in Sheep Brain
Barron et al.
Endocrinology 2009;150:3228-3236.
ABSTRACT
| FULL TEXT
A Novel Nicotinic Acetylcholine Receptor Subtype in Basal Forebrain Cholinergic Neurons with High Sensitivity to Amyloid Peptides
Liu et al.
J. Neurosci. 2009;29:918-929.
ABSTRACT
| FULL TEXT
Peripheral A{beta} subspecies as risk biomarkers of Alzheimer's disease
Schupf et al.
Proc. Natl. Acad. Sci. USA 2008;105:14052-14057.
ABSTRACT
| FULL TEXT
The Clinical Significance of Plasmatic Amyloid A{beta}-40 Peptide Levels in Alzheimer's Disease Patients Treated With Galantamine
Modrego et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2008;23:286-290.
ABSTRACT
Plasma Amyloid {beta}-Protein and C-reactive Protein in Relation to the Rate of Progression of Alzheimer Disease
Locascio et al.
Arch Neurol 2008;65:776-785.
ABSTRACT
| FULL TEXT
Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study
Lopez et al.
Neurology 2008;70:1664-1671.
ABSTRACT
| FULL TEXT
Amyloid-Associated Depression: A Prodromal Depression of Alzheimer Disease?
Sun et al.
Arch Gen Psychiatry 2008;65:542-550.
ABSTRACT
| FULL TEXT
Plasma {beta} Amyloid and the Risk of Alzheimer Disease and Dementia in Elderly Men: A Prospective, Population-Based Cohort Study
Sundelof et al.
Arch Neurol 2008;65:256-263.
ABSTRACT
| FULL TEXT
No association of CSF biomarkers with APOE{varepsilon}4, plaque and tangle burden in definite Alzheimer's disease
Engelborghs et al.
Brain 2007;130:2320-2326.
ABSTRACT
| FULL TEXT
Decreased cerebrospinal fluid amyloid beta (1-40) levels in frontotemporal lobar degeneration
Pijnenburg et al.
J. Neurol. Neurosurg. Psychiatry 2007;78:735-737.
ABSTRACT
| FULL TEXT
Elevated Plasma beta-Amyloid Peptide Abeta42 Levels, Incident Dementia, and Mortality in Down Syndrome
Schupf et al.
Arch Neurol 2007;64:1007-1013.
ABSTRACT
| FULL TEXT
Neurochemical aftermath of amateur boxing.
Zetterberg et al.
Arch Neurol 2006;63:1277-1280.
ABSTRACT
| FULL TEXT
Differential modulation of plasma {beta}-amyloid by insulin in patients with Alzheimer disease
Kulstad et al.
Neurology 2006;66:1506-1510.
ABSTRACT
| FULL TEXT
Effects of secreted oligomers of amyloid {beta}-protein on hippocampal synaptic plasticity: a potent role for trimers
Townsend et al.
J. Physiol. 2006;572:477-492.
ABSTRACT
| FULL TEXT
The Absence of ABCA1 Decreases Soluble ApoE Levels but Does Not Diminish Amyloid Deposition in Two Murine Models of Alzheimer Disease
Hirsch-Reinshagen et al.
J. Biol. Chem. 2005;280:43243-43256.
ABSTRACT
| FULL TEXT
Deletion of the Prostaglandin E2 EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease
Liang et al.
J. Neurosci. 2005;25:10180-10187.
ABSTRACT
| FULL TEXT
Differences and Similarities between Two Frequently Used Assays for Amyloid {beta} 42 in Cerebrospinal Fluid
Schoonenboom et al.
Clin. Chem. 2005;51:1057-1060.
FULL TEXT
Quantitative Measurement of Changes in Amyloid-{beta}(40) in the Rat Brain and Cerebrospinal Fluid following Treatment with the {gamma}-Secretase Inhibitor LY-411575 [N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]
Best et al.
J. Pharmacol. Exp. Ther. 2005;313:902-908.
ABSTRACT
| FULL TEXT
Protein markers for Alzheimer disease in the frontal cortex and cerebellum
Verdile et al.
Neurology 2004;63:1385-1392.
ABSTRACT
| FULL TEXT
Plasma levels of amyloid {beta}-protein 42 are increased in women with mild cognitive impairment
Assini et al.
Neurology 2004;63:828-831.
ABSTRACT
| FULL TEXT
{beta}-Amyloid Directly Inhibits Human {alpha}4{beta}2-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells
Wu et al.
J. Biol. Chem. 2004;279:37842-37851.
ABSTRACT
| FULL TEXT
An Attenuated Immune Response Is Sufficient to Enhance Cognition in an Alzheimer's Disease Mouse Model Immunized with Amyloid-{beta} Derivatives
Sigurdsson et al.
J. Neurosci. 2004;24:6277-6282.
ABSTRACT
| FULL TEXT
APOE {epsilon}4 allele is associated with reduced cerebrospinal fluid levels of A{beta}42
Prince et al.
Neurology 2004;62:2116-2118.
ABSTRACT
| FULL TEXT
Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-{beta} Precursor Protein and Amyloid-{beta} Deposition
Bowen et al.
J. Biol. Chem. 2004;279:20539-20545.
ABSTRACT
| FULL TEXT
Cerebrospinal Fluid Tau and {beta}-Amyloid: How Well Do These Biomarkers Reflect Autopsy-Confirmed Dementia Diagnoses?
Clark et al.
Arch Neurol 2003;60:1696-1702.
ABSTRACT
| FULL TEXT
Platelet Amyloid Precursor Protein Abnormalities in Mild Cognitive Impairment Predict Conversion to Dementia of Alzheimer Type: A 2-Year Follow-up Study
Borroni et al.
Arch Neurol 2003;60:1740-1744.
ABSTRACT
| FULL TEXT
Plasma A{beta}40 and A{beta}42 and Alzheimer's disease: Relation to age, mortality, and risk
Mayeux et al.
Neurology 2003;61:1185-1190.
ABSTRACT
| FULL TEXT
Age but Not Diagnosis Is the Main Predictor of Plasma Amyloid {beta}-Protein Levels
Fukumoto et al.
Arch Neurol 2003;60:958-964.
ABSTRACT
| FULL TEXT
The {gamma}-Secretase Inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl Ester Reduces A{beta} Levels in Vivo in Plasma and Cerebrospinal Fluid in Young (Plaque-Free) and Aged (Plaque-Bearing) Tg2576 Mice
Lanz et al.
J. Pharmacol. Exp. Ther. 2003;305:864-871.
ABSTRACT
| FULL TEXT
Decreased {beta}-Amyloid1-42 and Increased Tau Levels in Cerebrospinal Fluid of Patients With Alzheimer Disease
Sunderland et al.
JAMA 2003;289:2094-2103.
ABSTRACT
| FULL TEXT
Amyloid {beta}1-42 peptide alters the gating of human and mouse {alpha}-bungarotoxin-sensitive nicotinic receptors
Grassi et al.
J. Physiol. 2003;547:147-157.
ABSTRACT
| FULL TEXT
Oxidation of Methionine 35 Attenuates Formation of Amyloid beta -Peptide 1-40 Oligomers
Palmblad et al.
J. Biol. Chem. 2002;277:19506-19510.
ABSTRACT
| FULL TEXT
Brain to Plasma Amyloid-beta Efflux: a Measure of Brain Amyloid Burden in a Mouse Model of Alzheimer's Disease
DeMattos et al.
Science 2002;295:2264-2267.
ABSTRACT
| FULL TEXT
Alzheimer's Disease-related Overexpression of the Cation-dependent Mannose 6-Phosphate Receptor Increases Abeta Secretion. ROLE FOR ALTERED LYSOSOMAL HYDROLASE DISTRIBUTION IN beta -AMYLOIDOGENESIS
Mathews et al.
J. Biol. Chem. 2002;277:5299-5307.
ABSTRACT
| FULL TEXT
Abnormalities in the Pattern of Platelet Amyloid Precursor Protein Forms in Patients With Mild Cognitive Impairment and Alzheimer Disease
Padovani et al.
Arch Neurol 2002;59:71-75.
ABSTRACT
| FULL TEXT
Amyloid precursor protein in platelets: A peripheral marker for the diagnosis of sporadic AD
Padovani et al.
Neurology 2001;57:2243-2248.
ABSTRACT
| FULL TEXT
Nonfibrillar diffuse amyloid deposition due to a {gamma}42-secretase site mutation points to an essential role for N-truncated A{beta}42 in Alzheimer's disease
Kumar-Singh et al.
Hum Mol Genet 2000;9:2589-2598.
ABSTRACT
| FULL TEXT
|
