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Biological Markers of Alzheimer’s Disease
Neurobiology of Aging, Vol. 19, No. 2, pp. 149 –151, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0197-4580/98 $19.00 1 .00
PII:S0197-4580(98)00010-4
Biological Markers of Alzheimer’s Disease C. HOCK1 Department of Psychiatry, University of Basel, Switzerland ApoE genotype affects the age of onset and the degree of amyloid burden in patients with APP mutations.
THREE major purposes for biological markers for Alzheimer’s Disease (AD) have been suggested: diagnosis, treatment effect or progression, and prediction. Any potential marker must demonstrate sensitivity, specificity, reliability, and validity. A major obstacle to find a marker that fulfills these characteristics might be the long-term clinical and preclinical course of the disease. The duration of the clinical phase of the disease characterized by progressive cognitive decline is approximately 7 years from the occurence of first signs until death. It is assumed that the clinical phase is preceded by a 15–30-year preclinical period of continuous deposition of amyloid plaques and neurofibrillary tangles (and their constituent: paired helical filaments, PHF) (2,20). Figure 1 gives a schematic of a hypothetical model of the natural history of AD. Age of onset and rate of progression of the disease are largely determined by causative gene mutations and by genetic susceptibility factors. Several environmental risk factors may add to the individual genetic risk factors. If the assumption is true that a specific neuropathology precedes the clinical manifestation of the disease for years, or even decades, then a significant portion of the age-matched healthy controls may be preclinical AD patients. Therefore, when comparing AD patients to age-matched healthy controls using in vivo measures that are associated with the development of the specific histopathology of AD, a considerable overlap with age-matched healthy controls is to be expected.
BIOCHEMICAL MEASURES
As briefly stated above, biochemical measures may indicate three issues: first, that the clinically ill patient is an AD patient (and not vascular dementia or other neurodegenerative disorder, i.e., diagnosis and differential diagnosis); second, that the histopathological process has started or is ongoing (i.e., preclinical diagnosis, prediction, or detection of patients at risk); and third, measures that are closely associated with the underlying histopathology of AD may change with progression of the disease and/or may change during therapy (i.e., indicators of treatment effects). Assays established to date focussed on systems that were associated either with the characteristic histopathology in AD or with cell death and neurodegeneration in general. The first group of assays used protein markers that were derived from such histopathologically relevant molecules as amyloid precursor protein (APP), and its secreted soluble ectodomain (APPs), as well as amyloid b-peptide (Ab), and Tau protein, the major protein component of paired helical filaments. Soluble APP derivatives (6,11,15–17,19) including Ab (8,13,14,18,23) are present in human cerebrospinal fluid (CSF), but the suggestion that their concentrations are useful diagnostic markers for AD is controversial. While some investigators report no differences (14,23), others have reported a decrease in CSF levels of total Ab (18) or Ab1– 42 (8,13). CSF levels of APPs were reported to be decreased (15,17,19) or unchanged (6,11). By using ELISAs, many studies have shown highly significant elevation of CSF levels of Tau in AD compared with normal controls and other neurological or psychiatric disorders (7,9,12,25,26). Recently, one study showed dependence of CSF levels of Tau on apolipoprotein E4 allele frequency (5). More refined methods intend to quanititate Tau proteins that are phosphorylated at specific sites, e.g., Ser262, a potential critical site for binding of Tau to microtubules. All of these measures have in common that there are derived from the major histopathological hallmarks in AD, amyloid plaques and neurofibrillary tangles. Although some of these measures were significantly altered in AD when mean levels were compared to levels in control groups, there was still substantial overlap so that these measures were not considered to be sensitive enough for a biological marker. Nevertheless, those measures that might change over time, such as total Ab (decrease (14)) or Tau protein (increase (7) with progression of the disease), may serve as indicators of progression, or even, more importantly, indicators of treatment effects, e.g., effect of amyloid lowering agents. None of these
GENETIC MEASURES
Familial forms of AD with early onset can be caused by mutations of the amyloid b-protein precursor (APP) and the presenilin (PS) genes (PS1, PS2). These mutations are associated with increased ratios of Ab1– 42/Ab1– 40, and their overexpression in transgenic animals causes abnormally high levels of Ab1– 42 (for review see: (24)). Age of onset and the risk of getting sporadic AD are modulated by such genetic susceptibility factors as allelic variances of the apolipoprotein E (ApoE) gene (21). In addition, recently, Davis and colleagues (3) reported that AD patients show inherited high levels of a mutant form of the mitochondrial enzyme cytochrome oxidase. The search for other susceptibility genes in sporadic AD is a major research focus in many groups at the moment. The measurement of genetic risk factors may detect the releatively small number of autosomal dominant inherited familial AD and may allow here the prediction of an early onset of the disease and the determination of an individual risk parameter. The measurement of susceptibility genes may allow calculations of mean risks in a defined population, but does not predict age of onset or percent risk for an individual patient. Genetic factors may exert synergistic effects: Sorbi et al. (22) have shown that the
1 Address correspondence to: Christoph Hock, Psychiatrische Universita¨tsklinik (PUK), Wilhelm-Klein-Str. 27, CH-4025 Basel, Switzerland; E-mail: [email protected].
149
150
HOCK
FIG. 1. Hypothetical model of the natural history of Alzheimer’s disease.
candidate markers so far, were shown to be useful for prediction. In contrast to the aforementioned protein measures that were derived from amyloid plaques and neurofibrillary tangles, the second group of assays targeted other systems associated with neurodegeneration in AD and achieved in a greater seperation of AD patients from controls. Alterations in the regulation of intracellular calcium levels by potassium channels was demonstrated in fibroblasts (4) and lymphocytes (1) of AD patients. In addition, recently, Kennard et al. (10) reported that serum levels of the iron binding protein p97 were elevated in AD patients compared to controls. In that study, the serum p97 levels differentiated completely AD patients from controls, at least in a small number of patients. In addition, these levels were correlated with the duration of the disease. SOURCES OF POTENTIAL MARKERS
AD is the most common neurodegenerative disorder in the elderly. Therefore, diagnostic or predictive tests will be ordered by a large number of doctors, probably mostly general practitioners, neurologists, psychatrists, nursing home doctors, etc. Any assay that uses material that is easy accessible such as blood or urine will find widespread use. CSF analysis may be restricted to specialized centers, such as ambulatory care centers at universities. More invasive methods, such as olfactory biopsies, will be restricted to experienced and specialized units.
CONCLUSIONS
Several biochemical measures showed significant alterations in AD patients vs. controls, such as CSF levels of APPs, Ab1– 42, and Tau protein, intracellular calcium level regulation by potassium channels, and serum p97 levels. Some of these measures may change with progression of the disease (total Ab, Tau protein). Although some of these measures were significantly altered in AD when mean levels were compared to levels in control groups, there was still substantial overlap so that these measures were not considered to be sensitive enough to serve as a biological marker. However, if the assumption is true that the specific histopathology precedes the clinical manifestation of AD for years, or even decades, then a significant portion of the age-matched controls might be preclinical AD patients. Therefore, considerable overlap of a potential marker between AD patients and age-matched controls does not definitely exclude that the measure might be a sensitive and specific tool. New research designs for a biological marker of sporadic AD have to be developed that include not only healthy age-matched controls, but cover the whole age-range of healthy subjects in order to differentiate age-effects from effects of a beginning AD pathology (sensitivity). Further control groups should include other neurodegenerative, neurological and psychiatric disorders (e.g., major depression) (specificity).
REFERENCES 1. Bondy, B.; Hofmann, M.; Mu¨ller-Spahn, F.; Witzko, M.; Hock, C. The PHA-induced calcium signal in lymphocytes is altered after blockade of K1-channels in Alzheimer’s disease. J. Psychiat. Res. 30:217–227; 1996. 2. Davies, L.; Wolska, B.; Hilbich, C.; Multhaup, G.; Martins, R.; Simms, G.; Beyreuther, K.; Masters, C. L. A4 amyloid protein deposition and the diagnosis of Alzheimer’s disease. Neurology 38:1688 –1693; 1988. 3. Davis, R. E.; Miller, S.; Herrnstadt, C.; Ghosh, S. S.; Fahy, E.; Shinobu, L. A.; Galasko, D.; Thal, L. J.; Beal, M. F.; Howell, M.;
Davis Parker, W. Jr. Genetics mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 94:4526 – 4531; 1997. 4. Etcheberrigaray, R.; Ito, E.; Oka, K.; Tofel Grehl, B.; Gibson, G. E.; Alkon, D. L. Potassium channel dysfunction in fibroblasts identifies patients with Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 90: 8209 – 8213; 1993. 5. Golombowski, S.; Mu¨ller-Spahn, F.; Romig, H.; Mendla, K.; Hock, C. Dependence of cerebrospinal fluid Tau protein levels on apolipopro-
BIOLOGICAL MARKERS OF AD
6.
7.
8.
9. 10. 11.
12.
13.
14.
15.
tein E4 allele frequency in patients with Alzheimer’s disease. Neurosci. Lett. 225:1–3; 1997. Henriksson, T.; Barbour, R. M.; Braa, S.; Ward, P.; Freitz, L. C.; Johnson-Wood, K.; Chung, H. D.; Burke, W.; Reinikainen, K. J.; Riekkinen, P.; Schenk, D. B. Analysis and quantitation of the b-amyloid precursor protein in the cerebrospinal fluid of Alzheimer’s disease patients with a monoclonal antibody-based immunoassay. J. Neurochem. 56:1037– 42; 1991. Hock, C.; Golombowski, S.; Naser, W.; Mu¨ller-Spahn, F. Increased levels of Tau protein in cerebrospinal fluid of patients with Alzheimer‘s disease—Correlation with cognitive impairment. Ann. Neurol. 37:414 – 415; 1995. Ida, N.; Hartmann, T.; Pantel, J.; Schroder, J.; Zerfass, R.; Forstl, H.; Sandbrink, R.; Masters, C. L.; Beyreuther, K. Analysis of heterogenous bA4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J. Biol. Chem. 271:22908 – 22914; 1996. Jensen, M.; Basun, H.; Lannfelt, L. Increased cerebrospinal fluid tau in patients with Alzheimer’s disease. Neurosci. Lett. 186:189 –191; 1995. Kennard, M. L.; Feldman, H.; Yamada, T.; Jefferies, W. A. Serum levels of the iron binding protein p97 are elevated in Alzheimer’s disease. Nature Med. 2:1230 –1235; 1996. Kitaguchi, N.; Tokushima, Y.; Oishi, K.; Takahashi, Y.; Shiojiri, S.; Nakamura, S.; Tanaka, S.; Kodaira, R.; Ito, H. Determination of amyloid beta protein precursors harboring active form of proteinase inhibitor domains in cerebrospinal fluid of Alzheimer’s disease patients by trypsin-antibody sandwich ELISA. Biochem. Biophys. Res. Commun. 166:1453–9; 1990. Mori, H.; Hosoda, K.; Matsubara, E.; Nakamoto, T.; Furiya, Y.; Endoh, R.; Usami, M.; Shoji, M.; Maruyama, S.; Hirai, S. Tau in cerebrospinal fluids: establishment of the sandwich ELISA with antibody specific to the repeat sequence in tau. Neurosci. Lett. 186:181–183; 1995. Motter, R.; Vigo-Pelfrey, C.; Kholodenko, D.; Barbour, R.; JohnsonWood, K.; Galasko, D.; Chang, L.; Miller, B.; Clark, C.; Green, R.; Olson, D.; Southwick, P.; Wolfert, R.; Munroe, B.; Lieberburg, I.; Schenk, D. B. Reduction of b-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann. Neurol. 38:643– 648; 1995. Nitsch, R. M.; Rebeck, G. W.; Deng, M.; Richardson, U. I.; Tennis, M.; Schenk, D. B.; Vigo-Pelfrey, P.; Lieberburg, I.; Wurtman, R. J.; Hyman, B. T.; Growdon, J. H. Cerebrospinal fluid levels of amyloid b-protein in Alzheimer’s disease: Inverse correlation with severity of dementia and effect of apolipoprotein E genotype. Ann. Neurol. 37:512–518; 1995. van Nostrand, W. E.; Wagner, S. L.; Shankle, R. W.; Farrow, J. S.; Dick, M.; Rozemuller, J. M.; Kuiper, M. A.; Wolters, E. C.; Zimmermann, J.; Cotman, C. S.; Cunningham, D. D. Decreased levels of soluble amyloid b-protein precursor in cerebrospinal fluid of live
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Alzheimer9s disease patients. Proc. Natl. Acad. Sci. USA 89:2551– 2555; 1992. Palmert, M. R.; Berman Podlinsny, M.; Witker, D. S.; Oltersdorf, T.; Younkin, L. H.; Selkoe, D. J.; Younkin, S. G. The beta amyloid protein precursor of Alzheimer’s disease has soluble derivatives found in human brain and cerebrospinal fluid. Proc. Natl. Acad. Sci. USA 86:6338 – 6342; 1989. Palmert, M. R.; Usiak, M.; Mayeux, R.; Raskind, M.; Tourtellotte, W. W.; Younkin, S. G. Soluble derivates of the b amyloid protein precursor in cerebrospinal fluid: Alterations in normal aging and Alzheimer9s disease. Neurology 40:1028 –1034; 1990. Pirttila, T.; Kim, K. S.; Mehta, P. D.; Frey, H.; Wisniewski, H. M. Soluble amyloid b-protein in the cerebrospinal fluid from patients with Alzheimer’s disease, vascular dementia and controls. J. Neurol. Sci. 127:90 –5; 1994. Prior, R.; Mo¨nning, U.; Schreiter-Gasser, U.; Weidemann, U.; Weidemann, A.; Blennow, K.; Gottfries, C. G.; Masters, C. L.; Beyreuther, K. Quantitative changes in the amyloid bA4 precursor protein in Alzheimer cerebrospinal fluid. Neurosci. Lett. 124:69 –73; 1991. Rumble, B.; Retallack, R.; Hilbich, M.; Simms, G.; Multhaup, G.; Martins, R.; Hockey, A.; Montgomery, P.; Beyreuther, K.; Masters, C. L. Amyloid A4 protein and ist precursor in Down9s syndrome and Alzheimer9s disease. N. Engl. J. Med. 320:1446 –1452; 1989. Saunders, A. M.; Strittmatter, W. J.; Schmechel, D.; St. GeorgeHyslop, P. H.; Pericak-Vance, M. A.; Joo, S. H.; Rosi, B. L.; Gusella, J. F.; Crapper-McLachlan, D. R.; Alberts, M. J.; Hulette, C.; Crain, B.; Goldgaber, D.; Roses, A. D. Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472; 1993. Sorbi, S.; Nacmias, B.; Forleo, P.; Piacentini, S.; Latorraca, S.; Amaducci, L. Epistatic effect of APP717 Mutation and Apolipoprotein E Genotype in Familial Alzheimer’s Disease. Ann. Neurol. 38:124 – 127; 1995. Southwick, P. C.; Yamagata, S. K.; Echols, C. L.; Higson, G. J.; Neynaber, S. A.; Parson, R. E.; Munroe, W. A. Assessment of amyloid b-protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer’s disease. J. Neurochem. 66:259 –265; 1996. Tanzi, R. E.; Kovacs, D. M.; Kim, T. W.; Mori, R. D.; Guenette, S. Y.; Wasco, W. The presenilin genes and their role in ealy onset familial Alzheimer’s disease. Alzheimer’s Dis. Rev. 1:91–98; 1996. Vandermeeren, M.; Mercken, M.; Vanmechelen, E., et al. Detection of tau proteins in normal and Alzheimer9s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J. Neurochem. 61:1828 –1834; 1993. Vigo-Pelfrey, C.; Seubert, P.; Barbour, R.; Blomquist, C.; Lee, M.; Lee, D.; Coria, F.; Chang, L.; Miller, B.; Lieberburg, I.; Schenk, D. Elevation of microtubule-associated protein tau in the cerebrospinal fluid of Alzheimer’s patients. Neurology 45:188 –793; 1995.
PII:S0197-4580(98)00010-4
Biological Markers of Alzheimer’s Disease C. HOCK1 Department of Psychiatry, University of Basel, Switzerland ApoE genotype affects the age of onset and the degree of amyloid burden in patients with APP mutations.
THREE major purposes for biological markers for Alzheimer’s Disease (AD) have been suggested: diagnosis, treatment effect or progression, and prediction. Any potential marker must demonstrate sensitivity, specificity, reliability, and validity. A major obstacle to find a marker that fulfills these characteristics might be the long-term clinical and preclinical course of the disease. The duration of the clinical phase of the disease characterized by progressive cognitive decline is approximately 7 years from the occurence of first signs until death. It is assumed that the clinical phase is preceded by a 15–30-year preclinical period of continuous deposition of amyloid plaques and neurofibrillary tangles (and their constituent: paired helical filaments, PHF) (2,20). Figure 1 gives a schematic of a hypothetical model of the natural history of AD. Age of onset and rate of progression of the disease are largely determined by causative gene mutations and by genetic susceptibility factors. Several environmental risk factors may add to the individual genetic risk factors. If the assumption is true that a specific neuropathology precedes the clinical manifestation of the disease for years, or even decades, then a significant portion of the age-matched healthy controls may be preclinical AD patients. Therefore, when comparing AD patients to age-matched healthy controls using in vivo measures that are associated with the development of the specific histopathology of AD, a considerable overlap with age-matched healthy controls is to be expected.
BIOCHEMICAL MEASURES
As briefly stated above, biochemical measures may indicate three issues: first, that the clinically ill patient is an AD patient (and not vascular dementia or other neurodegenerative disorder, i.e., diagnosis and differential diagnosis); second, that the histopathological process has started or is ongoing (i.e., preclinical diagnosis, prediction, or detection of patients at risk); and third, measures that are closely associated with the underlying histopathology of AD may change with progression of the disease and/or may change during therapy (i.e., indicators of treatment effects). Assays established to date focussed on systems that were associated either with the characteristic histopathology in AD or with cell death and neurodegeneration in general. The first group of assays used protein markers that were derived from such histopathologically relevant molecules as amyloid precursor protein (APP), and its secreted soluble ectodomain (APPs), as well as amyloid b-peptide (Ab), and Tau protein, the major protein component of paired helical filaments. Soluble APP derivatives (6,11,15–17,19) including Ab (8,13,14,18,23) are present in human cerebrospinal fluid (CSF), but the suggestion that their concentrations are useful diagnostic markers for AD is controversial. While some investigators report no differences (14,23), others have reported a decrease in CSF levels of total Ab (18) or Ab1– 42 (8,13). CSF levels of APPs were reported to be decreased (15,17,19) or unchanged (6,11). By using ELISAs, many studies have shown highly significant elevation of CSF levels of Tau in AD compared with normal controls and other neurological or psychiatric disorders (7,9,12,25,26). Recently, one study showed dependence of CSF levels of Tau on apolipoprotein E4 allele frequency (5). More refined methods intend to quanititate Tau proteins that are phosphorylated at specific sites, e.g., Ser262, a potential critical site for binding of Tau to microtubules. All of these measures have in common that there are derived from the major histopathological hallmarks in AD, amyloid plaques and neurofibrillary tangles. Although some of these measures were significantly altered in AD when mean levels were compared to levels in control groups, there was still substantial overlap so that these measures were not considered to be sensitive enough for a biological marker. Nevertheless, those measures that might change over time, such as total Ab (decrease (14)) or Tau protein (increase (7) with progression of the disease), may serve as indicators of progression, or even, more importantly, indicators of treatment effects, e.g., effect of amyloid lowering agents. None of these
GENETIC MEASURES
Familial forms of AD with early onset can be caused by mutations of the amyloid b-protein precursor (APP) and the presenilin (PS) genes (PS1, PS2). These mutations are associated with increased ratios of Ab1– 42/Ab1– 40, and their overexpression in transgenic animals causes abnormally high levels of Ab1– 42 (for review see: (24)). Age of onset and the risk of getting sporadic AD are modulated by such genetic susceptibility factors as allelic variances of the apolipoprotein E (ApoE) gene (21). In addition, recently, Davis and colleagues (3) reported that AD patients show inherited high levels of a mutant form of the mitochondrial enzyme cytochrome oxidase. The search for other susceptibility genes in sporadic AD is a major research focus in many groups at the moment. The measurement of genetic risk factors may detect the releatively small number of autosomal dominant inherited familial AD and may allow here the prediction of an early onset of the disease and the determination of an individual risk parameter. The measurement of susceptibility genes may allow calculations of mean risks in a defined population, but does not predict age of onset or percent risk for an individual patient. Genetic factors may exert synergistic effects: Sorbi et al. (22) have shown that the
1 Address correspondence to: Christoph Hock, Psychiatrische Universita¨tsklinik (PUK), Wilhelm-Klein-Str. 27, CH-4025 Basel, Switzerland; E-mail: [email protected].
149
150
HOCK
FIG. 1. Hypothetical model of the natural history of Alzheimer’s disease.
candidate markers so far, were shown to be useful for prediction. In contrast to the aforementioned protein measures that were derived from amyloid plaques and neurofibrillary tangles, the second group of assays targeted other systems associated with neurodegeneration in AD and achieved in a greater seperation of AD patients from controls. Alterations in the regulation of intracellular calcium levels by potassium channels was demonstrated in fibroblasts (4) and lymphocytes (1) of AD patients. In addition, recently, Kennard et al. (10) reported that serum levels of the iron binding protein p97 were elevated in AD patients compared to controls. In that study, the serum p97 levels differentiated completely AD patients from controls, at least in a small number of patients. In addition, these levels were correlated with the duration of the disease. SOURCES OF POTENTIAL MARKERS
AD is the most common neurodegenerative disorder in the elderly. Therefore, diagnostic or predictive tests will be ordered by a large number of doctors, probably mostly general practitioners, neurologists, psychatrists, nursing home doctors, etc. Any assay that uses material that is easy accessible such as blood or urine will find widespread use. CSF analysis may be restricted to specialized centers, such as ambulatory care centers at universities. More invasive methods, such as olfactory biopsies, will be restricted to experienced and specialized units.
CONCLUSIONS
Several biochemical measures showed significant alterations in AD patients vs. controls, such as CSF levels of APPs, Ab1– 42, and Tau protein, intracellular calcium level regulation by potassium channels, and serum p97 levels. Some of these measures may change with progression of the disease (total Ab, Tau protein). Although some of these measures were significantly altered in AD when mean levels were compared to levels in control groups, there was still substantial overlap so that these measures were not considered to be sensitive enough to serve as a biological marker. However, if the assumption is true that the specific histopathology precedes the clinical manifestation of AD for years, or even decades, then a significant portion of the age-matched controls might be preclinical AD patients. Therefore, considerable overlap of a potential marker between AD patients and age-matched controls does not definitely exclude that the measure might be a sensitive and specific tool. New research designs for a biological marker of sporadic AD have to be developed that include not only healthy age-matched controls, but cover the whole age-range of healthy subjects in order to differentiate age-effects from effects of a beginning AD pathology (sensitivity). Further control groups should include other neurodegenerative, neurological and psychiatric disorders (e.g., major depression) (specificity).
REFERENCES 1. Bondy, B.; Hofmann, M.; Mu¨ller-Spahn, F.; Witzko, M.; Hock, C. The PHA-induced calcium signal in lymphocytes is altered after blockade of K1-channels in Alzheimer’s disease. J. Psychiat. Res. 30:217–227; 1996. 2. Davies, L.; Wolska, B.; Hilbich, C.; Multhaup, G.; Martins, R.; Simms, G.; Beyreuther, K.; Masters, C. L. A4 amyloid protein deposition and the diagnosis of Alzheimer’s disease. Neurology 38:1688 –1693; 1988. 3. Davis, R. E.; Miller, S.; Herrnstadt, C.; Ghosh, S. S.; Fahy, E.; Shinobu, L. A.; Galasko, D.; Thal, L. J.; Beal, M. F.; Howell, M.;
Davis Parker, W. Jr. Genetics mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 94:4526 – 4531; 1997. 4. Etcheberrigaray, R.; Ito, E.; Oka, K.; Tofel Grehl, B.; Gibson, G. E.; Alkon, D. L. Potassium channel dysfunction in fibroblasts identifies patients with Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 90: 8209 – 8213; 1993. 5. Golombowski, S.; Mu¨ller-Spahn, F.; Romig, H.; Mendla, K.; Hock, C. Dependence of cerebrospinal fluid Tau protein levels on apolipopro-
BIOLOGICAL MARKERS OF AD
6.
7.
8.
9. 10. 11.
12.
13.
14.
15.
tein E4 allele frequency in patients with Alzheimer’s disease. Neurosci. Lett. 225:1–3; 1997. Henriksson, T.; Barbour, R. M.; Braa, S.; Ward, P.; Freitz, L. C.; Johnson-Wood, K.; Chung, H. D.; Burke, W.; Reinikainen, K. J.; Riekkinen, P.; Schenk, D. B. Analysis and quantitation of the b-amyloid precursor protein in the cerebrospinal fluid of Alzheimer’s disease patients with a monoclonal antibody-based immunoassay. J. Neurochem. 56:1037– 42; 1991. Hock, C.; Golombowski, S.; Naser, W.; Mu¨ller-Spahn, F. Increased levels of Tau protein in cerebrospinal fluid of patients with Alzheimer‘s disease—Correlation with cognitive impairment. Ann. Neurol. 37:414 – 415; 1995. Ida, N.; Hartmann, T.; Pantel, J.; Schroder, J.; Zerfass, R.; Forstl, H.; Sandbrink, R.; Masters, C. L.; Beyreuther, K. Analysis of heterogenous bA4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J. Biol. Chem. 271:22908 – 22914; 1996. Jensen, M.; Basun, H.; Lannfelt, L. Increased cerebrospinal fluid tau in patients with Alzheimer’s disease. Neurosci. Lett. 186:189 –191; 1995. Kennard, M. L.; Feldman, H.; Yamada, T.; Jefferies, W. A. Serum levels of the iron binding protein p97 are elevated in Alzheimer’s disease. Nature Med. 2:1230 –1235; 1996. Kitaguchi, N.; Tokushima, Y.; Oishi, K.; Takahashi, Y.; Shiojiri, S.; Nakamura, S.; Tanaka, S.; Kodaira, R.; Ito, H. Determination of amyloid beta protein precursors harboring active form of proteinase inhibitor domains in cerebrospinal fluid of Alzheimer’s disease patients by trypsin-antibody sandwich ELISA. Biochem. Biophys. Res. Commun. 166:1453–9; 1990. Mori, H.; Hosoda, K.; Matsubara, E.; Nakamoto, T.; Furiya, Y.; Endoh, R.; Usami, M.; Shoji, M.; Maruyama, S.; Hirai, S. Tau in cerebrospinal fluids: establishment of the sandwich ELISA with antibody specific to the repeat sequence in tau. Neurosci. Lett. 186:181–183; 1995. Motter, R.; Vigo-Pelfrey, C.; Kholodenko, D.; Barbour, R.; JohnsonWood, K.; Galasko, D.; Chang, L.; Miller, B.; Clark, C.; Green, R.; Olson, D.; Southwick, P.; Wolfert, R.; Munroe, B.; Lieberburg, I.; Schenk, D. B. Reduction of b-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann. Neurol. 38:643– 648; 1995. Nitsch, R. M.; Rebeck, G. W.; Deng, M.; Richardson, U. I.; Tennis, M.; Schenk, D. B.; Vigo-Pelfrey, P.; Lieberburg, I.; Wurtman, R. J.; Hyman, B. T.; Growdon, J. H. Cerebrospinal fluid levels of amyloid b-protein in Alzheimer’s disease: Inverse correlation with severity of dementia and effect of apolipoprotein E genotype. Ann. Neurol. 37:512–518; 1995. van Nostrand, W. E.; Wagner, S. L.; Shankle, R. W.; Farrow, J. S.; Dick, M.; Rozemuller, J. M.; Kuiper, M. A.; Wolters, E. C.; Zimmermann, J.; Cotman, C. S.; Cunningham, D. D. Decreased levels of soluble amyloid b-protein precursor in cerebrospinal fluid of live
151
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
26.
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