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Diagnostic Markers for Alzheimer’s Disease
Neurobiology of Aging, Vol. 19, No. 2, pp. 131–132, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0197-4580/98 $19.00 1 .00
PII:S0197-4580(98)00023-2
Diagnostic Markers for Alzheimer’s Disease M. KENNARD Biotechnology Laboratory, Room 237-Westbrook Building, University of British Columbia, 6174 University Boulevard, Vancouver, British Columbia, Canada V6T 1Z3 THERE is currently no specific test for the diagnosis of Alzheimer’s disease (AD). No biochemical or genetic markers have been identified that clearly indicate the presence of AD, although a few relatively non-specific commercial tests have been recently introduced to aid the physician. AD is, therefore, diagnosed by excluding other conditions and then applying a set of clinical parameters before arriving at a probable AD diagnosis. A definite diagnosis is still based on histopathological examination of the brain after death. Because 60 – 66% of all dementia patients have AD of some degree, 2/3 of dementia patients will always be correctly identified as AD patients, even without diagnostic testing. By using patient history data, brain imaging, and psychosocial testing, 80 –90% of patients can be correctly diagnosed at the present time. However, none of the assessments and testing required to achieve this accuracy are simple, quick, or inexpensive, and cannot be used for routine screening of the general population for AD. Furthermore, the currently available tests are generally unable to diagnose AD early in its development and are also inadequate for measuring the impact of different AD therapies. Currently, the success of therapeutic intervention is determined through psychosocial testing, which is, unfortunately, unable to detect changes over short periods of time and thus makes it difficult to asses the usefulness of short-term therapeutic drug trials aimed at halting or reducing the affects of AD. Another major limitation to the present methods of testing is their inability to diagnose AD early in its development. Primary care physicians, who generally see the patients during the early stages of the disease, seem to widely under-diagnose the disease. Because it appears there is considerable brain damage prior to observable symptoms of AD, it is extremely important to be able to identify AD in its early stages, and, ultimately, presymtomatically. Early therapeutic intervention may be able to halt or even reverse AD before extensive brain damage has occurred. Lack of identifying AD at an early stage may lead to therapies that could worsen AD (e.g., by using anticholinergic drugs). Furthermore, early diagnosis would give families more time to plan for proper care of the AD patient. It would also be useful to be able to eliminate the diagnosis of AD for conditions that mimic its symptoms, such as depression, poor nutrition, or stroke. Considerable interest has been directed at the genetic causes of AD, and mutations in several genes have been shown to confer susceptibility in a small number of familial AD cases. For example, having the ApoE4 gene on chromosome 19 results in an increased probability in developing AD. Unfortunately, up to 90% of those who are homozygous for ApoE4 do not develop AD, and 40% of those with AD do not have any ApoE4 alleles. The discovery of these genes will have considerable value in determining the presdisposition of certain individuals to develop AD. However, genetic assessment, on its own, will not be useful in the
diagnosis or monitoring of AD, especially because the tests take time and cannot be routinely performed in a doctor’s clinic. The true value of these discoveries will lie in elucidating the causes and development of the disease. The lack of an AD diagnostic has been a severe barrier to the development of new drugs, particularly with regards to the selection of patients and controls for clinical trials and assessing the response to drug therapy. Clinical trials of AD therapies currently use psychosocial measures to determine the outcome of the intervention. Long-term clinical trial results (6 months to over a year) are difficult to interpret unless they include a large number of patients, while changes in test scores are very difficult to detect in shorter drug trials. Furthermore, the various psychosocial tests used to asses the trial are highly susceptible to variations among investigators, test administrators, and day-to-day fluctuations in the patient’s mood or behavior. Scores are often affected by educational level, culture, subject age, and the ability of the patient to learn the test when repeated over a period of time. It is also difficult to determine whether small changes in scores over short periods of time are meaningful or significant, and testing is generally required over a period of 6 months to a year or even longer. Current treatment options are limited, because by the time treatment starts there is already extensive neurological damage. It is, therefore, believed that many of the therapeutics previously tested for AD did not work because brain damage was too severe. Identifying AD in its early stages would provide increased opportunity for therapeutic intervention. In the U.S., it has been estimated that delaying the onset of AD by only 5 years will reduce by half the number of people suffering from symptoms and the total direct costs of managing the disease. Urinanalysis and blood tests are conducted to identify patients who have other dementias to AD. No biochemical markers have been identified that specifically identify the presence of AD. Although some commercial tests have recently been introduced to aid diagnosis, such as tau protein, Ab42, or neural thread protein found in the cerebrospinal fluid (CSF). Unfortunately, these tests are not routine and cannot be conducted in hospital laboratories or doctors’ clinics and must be carried out by the diagnostic companies themselves. Other markers such as amyloid precursor protein, a1-antichymotrypsin, and ubiquitin, which initially showed promise, have now provided results that tend to be inconclusive, contradictory, and with considerable overlap. All these tests are based on CSF samples (obtained by lumbar puncture), which is not a routine or simple testing procedure. The search for a specific biochemical marker is, therefore, still essential for the assessment and management of AD, especially in the areas of: 1) diagnosis, especially early on in the disease; 2) monitoring the effect of therapeutic intervention; 3) routine screening of the general population, i.e., those over 50 years of age; and 4) wrongful diagnosis 131
132 of AD. A quick and simple test based on a biochemical marker could also reduce the cost and time of current diagnosis, which can cost up to $3,000 per patient and take several months to a few years. An ideal test for AD would: 1) have a high sensitivity, able to identify close to 100% of AD patients with no false positives or false negatives; 2) have a high specificity, able to differentiate AD from other dementias, from normal aging and from other causes of cognitive impairment; 3) be able to diagnose AD at the early disease stage or presymptomatically before symptoms progress to a life-disrupting level; 4) be able to distinguish between familial (early-onset) and sporadic (late-onset) AD; 5) be relatively inexpensive as other diagnostic procedures will still need to be conducted to rule out other, treatable, dementias that may co-exist with AD; and 6) be convenient to use and not threatening to the patient. More specifically, the ideal test would also: 7) be based on an easily available bodily fluid such as blood (plasma or serum), urine, or saliva, as opposed to CSF; 8) be useful in monitoring the progression of the disease and the effects of different treatments on disease progression/slowdown, i.e., provide a useful significant measure of change over short periods of time; and 9) be sufficiently simple to be adapted to a test that may be routinely used for widespread screening of the elderly. As mentioned earlier, all the presently available tests, commercial or otherwise, do not meet these criteria and have few, if any, of the ideal attributes. Furthermore, the currently available assays, which aid the diagnosis of AD, measure biological markers in the CSF. Spinal tapping is unlikely to ever become a routine procedure. In addition, the current commercial tests are obviously not user friendly, because samples need to be sent to the diagnostic laboratory for analysis. Although brain imaging techniques such as magnetic resonance imaging, nuclear magnetic resonance spectroscopy, or positron emission tomography are playing an increasingly important role in supporting the diagnosis and early detection
KENNARD of AD, widespread screening using such techniques is not really feasible. The techniques require highly expensive equipment and major technical expertise and support. Furthermore, as with genetic testing, there is a considerable overlap in results between those with AD and those without it. Thus, in conclusion, the need to develop an AD diagnostic marker is still necessary for the diagnosis, screening, and monitoring of AD. In order to be useful, the test must be simple, cheap, and user-friendly, otherwise its application will be limited. Thus, future research should be directed at accessible bodily fluids. Although there are substantial benefits to an accurate, easy-to-use AD diagnostic test, there are also some concerns that become important once a diagnostic becomes available, particularly one that could be used as a screening test to detect the disease in its early presymptomatic stage. Because AD is currently untreatable and unpreventable, there may be ethical, emotional, and financial problems facing families and individuals using the test. Extensive counseling guidelines will have to be developed for this situation. These concerns and questions will also have to be addressed by employers and health care insurance agencies and policies developed. There is even the question of whether the results of a diagnostic test should be made available to these agencies or employers. One final consideration is that there may be a danger in trying to find a unique, ideal, and perfect biochemical marker for AD. The search may become too much of the pursuit of an AD diagnostic “holy grail.” It must be remembered that because so many abnormalities are present in the AD brain, AD may consist of several causes with varying symptoms that may result in the disruption of several markers. Thus, it may not be possible to identify a single biochemical marker for AD and more than one may be needed for the 100% diagnosis of AD. Furthermore, if the test is based on measuring changes in a naturally occurring biological compound, as is the case with the present biological markers, then it must be assumed that there will probably always be some overlap between the AD and normal populations. It is likely that a final diagnostic for AD will be based on a combination of tests, which may include several biological markers and possibly a genetic test.
PII:S0197-4580(98)00023-2
Diagnostic Markers for Alzheimer’s Disease M. KENNARD Biotechnology Laboratory, Room 237-Westbrook Building, University of British Columbia, 6174 University Boulevard, Vancouver, British Columbia, Canada V6T 1Z3 THERE is currently no specific test for the diagnosis of Alzheimer’s disease (AD). No biochemical or genetic markers have been identified that clearly indicate the presence of AD, although a few relatively non-specific commercial tests have been recently introduced to aid the physician. AD is, therefore, diagnosed by excluding other conditions and then applying a set of clinical parameters before arriving at a probable AD diagnosis. A definite diagnosis is still based on histopathological examination of the brain after death. Because 60 – 66% of all dementia patients have AD of some degree, 2/3 of dementia patients will always be correctly identified as AD patients, even without diagnostic testing. By using patient history data, brain imaging, and psychosocial testing, 80 –90% of patients can be correctly diagnosed at the present time. However, none of the assessments and testing required to achieve this accuracy are simple, quick, or inexpensive, and cannot be used for routine screening of the general population for AD. Furthermore, the currently available tests are generally unable to diagnose AD early in its development and are also inadequate for measuring the impact of different AD therapies. Currently, the success of therapeutic intervention is determined through psychosocial testing, which is, unfortunately, unable to detect changes over short periods of time and thus makes it difficult to asses the usefulness of short-term therapeutic drug trials aimed at halting or reducing the affects of AD. Another major limitation to the present methods of testing is their inability to diagnose AD early in its development. Primary care physicians, who generally see the patients during the early stages of the disease, seem to widely under-diagnose the disease. Because it appears there is considerable brain damage prior to observable symptoms of AD, it is extremely important to be able to identify AD in its early stages, and, ultimately, presymtomatically. Early therapeutic intervention may be able to halt or even reverse AD before extensive brain damage has occurred. Lack of identifying AD at an early stage may lead to therapies that could worsen AD (e.g., by using anticholinergic drugs). Furthermore, early diagnosis would give families more time to plan for proper care of the AD patient. It would also be useful to be able to eliminate the diagnosis of AD for conditions that mimic its symptoms, such as depression, poor nutrition, or stroke. Considerable interest has been directed at the genetic causes of AD, and mutations in several genes have been shown to confer susceptibility in a small number of familial AD cases. For example, having the ApoE4 gene on chromosome 19 results in an increased probability in developing AD. Unfortunately, up to 90% of those who are homozygous for ApoE4 do not develop AD, and 40% of those with AD do not have any ApoE4 alleles. The discovery of these genes will have considerable value in determining the presdisposition of certain individuals to develop AD. However, genetic assessment, on its own, will not be useful in the
diagnosis or monitoring of AD, especially because the tests take time and cannot be routinely performed in a doctor’s clinic. The true value of these discoveries will lie in elucidating the causes and development of the disease. The lack of an AD diagnostic has been a severe barrier to the development of new drugs, particularly with regards to the selection of patients and controls for clinical trials and assessing the response to drug therapy. Clinical trials of AD therapies currently use psychosocial measures to determine the outcome of the intervention. Long-term clinical trial results (6 months to over a year) are difficult to interpret unless they include a large number of patients, while changes in test scores are very difficult to detect in shorter drug trials. Furthermore, the various psychosocial tests used to asses the trial are highly susceptible to variations among investigators, test administrators, and day-to-day fluctuations in the patient’s mood or behavior. Scores are often affected by educational level, culture, subject age, and the ability of the patient to learn the test when repeated over a period of time. It is also difficult to determine whether small changes in scores over short periods of time are meaningful or significant, and testing is generally required over a period of 6 months to a year or even longer. Current treatment options are limited, because by the time treatment starts there is already extensive neurological damage. It is, therefore, believed that many of the therapeutics previously tested for AD did not work because brain damage was too severe. Identifying AD in its early stages would provide increased opportunity for therapeutic intervention. In the U.S., it has been estimated that delaying the onset of AD by only 5 years will reduce by half the number of people suffering from symptoms and the total direct costs of managing the disease. Urinanalysis and blood tests are conducted to identify patients who have other dementias to AD. No biochemical markers have been identified that specifically identify the presence of AD. Although some commercial tests have recently been introduced to aid diagnosis, such as tau protein, Ab42, or neural thread protein found in the cerebrospinal fluid (CSF). Unfortunately, these tests are not routine and cannot be conducted in hospital laboratories or doctors’ clinics and must be carried out by the diagnostic companies themselves. Other markers such as amyloid precursor protein, a1-antichymotrypsin, and ubiquitin, which initially showed promise, have now provided results that tend to be inconclusive, contradictory, and with considerable overlap. All these tests are based on CSF samples (obtained by lumbar puncture), which is not a routine or simple testing procedure. The search for a specific biochemical marker is, therefore, still essential for the assessment and management of AD, especially in the areas of: 1) diagnosis, especially early on in the disease; 2) monitoring the effect of therapeutic intervention; 3) routine screening of the general population, i.e., those over 50 years of age; and 4) wrongful diagnosis 131
132 of AD. A quick and simple test based on a biochemical marker could also reduce the cost and time of current diagnosis, which can cost up to $3,000 per patient and take several months to a few years. An ideal test for AD would: 1) have a high sensitivity, able to identify close to 100% of AD patients with no false positives or false negatives; 2) have a high specificity, able to differentiate AD from other dementias, from normal aging and from other causes of cognitive impairment; 3) be able to diagnose AD at the early disease stage or presymptomatically before symptoms progress to a life-disrupting level; 4) be able to distinguish between familial (early-onset) and sporadic (late-onset) AD; 5) be relatively inexpensive as other diagnostic procedures will still need to be conducted to rule out other, treatable, dementias that may co-exist with AD; and 6) be convenient to use and not threatening to the patient. More specifically, the ideal test would also: 7) be based on an easily available bodily fluid such as blood (plasma or serum), urine, or saliva, as opposed to CSF; 8) be useful in monitoring the progression of the disease and the effects of different treatments on disease progression/slowdown, i.e., provide a useful significant measure of change over short periods of time; and 9) be sufficiently simple to be adapted to a test that may be routinely used for widespread screening of the elderly. As mentioned earlier, all the presently available tests, commercial or otherwise, do not meet these criteria and have few, if any, of the ideal attributes. Furthermore, the currently available assays, which aid the diagnosis of AD, measure biological markers in the CSF. Spinal tapping is unlikely to ever become a routine procedure. In addition, the current commercial tests are obviously not user friendly, because samples need to be sent to the diagnostic laboratory for analysis. Although brain imaging techniques such as magnetic resonance imaging, nuclear magnetic resonance spectroscopy, or positron emission tomography are playing an increasingly important role in supporting the diagnosis and early detection
KENNARD of AD, widespread screening using such techniques is not really feasible. The techniques require highly expensive equipment and major technical expertise and support. Furthermore, as with genetic testing, there is a considerable overlap in results between those with AD and those without it. Thus, in conclusion, the need to develop an AD diagnostic marker is still necessary for the diagnosis, screening, and monitoring of AD. In order to be useful, the test must be simple, cheap, and user-friendly, otherwise its application will be limited. Thus, future research should be directed at accessible bodily fluids. Although there are substantial benefits to an accurate, easy-to-use AD diagnostic test, there are also some concerns that become important once a diagnostic becomes available, particularly one that could be used as a screening test to detect the disease in its early presymptomatic stage. Because AD is currently untreatable and unpreventable, there may be ethical, emotional, and financial problems facing families and individuals using the test. Extensive counseling guidelines will have to be developed for this situation. These concerns and questions will also have to be addressed by employers and health care insurance agencies and policies developed. There is even the question of whether the results of a diagnostic test should be made available to these agencies or employers. One final consideration is that there may be a danger in trying to find a unique, ideal, and perfect biochemical marker for AD. The search may become too much of the pursuit of an AD diagnostic “holy grail.” It must be remembered that because so many abnormalities are present in the AD brain, AD may consist of several causes with varying symptoms that may result in the disruption of several markers. Thus, it may not be possible to identify a single biochemical marker for AD and more than one may be needed for the 100% diagnosis of AD. Furthermore, if the test is based on measuring changes in a naturally occurring biological compound, as is the case with the present biological markers, then it must be assumed that there will probably always be some overlap between the AD and normal populations. It is likely that a final diagnostic for AD will be based on a combination of tests, which may include several biological markers and possibly a genetic test.