Alzheimer's Disease ("AD") is a dementing disorder characterized by progressive impairments in memory and cognition typically occurring in later life; and is associated with a multiplicity of structural, chemical and functional abnormalities involving regions of the brain concerned with cognition and memory and particular populations of nerve cells. This form of dementia was first reported by Alois Alzheimer in 1907 when he described a particular disease of the cerebral cortex in a 51-year-old woman suffering from an inexorably progressive dementing disorder. Although other forms of dementia were known and well characterized at the time of Alzheimer's clinical report, his patient was found to be clinically and pathologically unusual, based on the relatively young age of the patient and the presence of the then newly described intra-cellular inclusions which have come to be known as neurofibrillary tangles ("NFTs"). In recognition of this unique combination of clinical and pathological features, the term "Alzheimer's Disease" subsequently came into common usage.
Today, Alzheimer's Disease is considered to be one of the forthcoming scourges of the 21st century. This is due in major part to the aging population in concert with data indicating a marked increase in the incidence of dementia with advancing age; and in part to epidemiologic studies measuring the current prevalence of such disorders which suggest that the dementia occurs in up to 10% of individuals over the age of 65. It is estimated that in the United States alone, as many as 4 million individuals may be affected with Alzheimer's Disease; and the cost of caring for such individuals is well over 80 billion dollars annually and increasing rapidly.
Since the recognition of this form of dementia as a specific disorder, many different neurobiologic approaches have been undertaken to studying and understanding the nature and the mechanism of action for Alzheimer's Disease, with a view to possible future therapeutic treatments and/or prevention. Representative of the range and diversity of these many neurobiologic approaches are those listed within Table A below.
TABLE A __________________________________________________________________________ Neurobiologic Approaches to the Study of Alzheimer's Disease* Biologic Measures Methods Examples __________________________________________________________________________ Brain metabolism In vivo imaging studies Reduced glucose utilization in neocortex, esp. parietal and temporal areas Histology of brain Histochemistry, /A4 immunoreactive plaques immunocytochemistry in neocortex and hippocampus Quantitation of Morphometric methods Reduced number of neurons in pathology basal forebrain cholinergic system Neuron size and Golgi Stains Abnormal dendritic Shape arborizations Ultrastructure Electron microscopy, PHF in NFT and /A4 fibrils in immunocytochemistry plaques Transmitters and Assays of markers Reduced levels of ChAT, enzymes somatostatin, and CRF in cortex Receptors Binding Assays in vitro Reduced cortical somatostatin autoradiography receptors and increased cortical CRF receptors Proteins in abnormal Purification of constituents, Decoration of PHF with organelles analyses of proteins and antineurofilament and other components, antiau antibodies; tubulinlike immunocytochemistry immunoreactivity in GVD; actin freeze-fracture/deep-etch in Hirano bodies; /A4 in plaque cores and congo philic angiopathy Proteins and their Immunoblots, Phosphorylated 200-kD modifications immunocytochemistry, in neurofilament A68 and tau vitro incorporation of amino associated with NFT; aberrant acids processing of APP and PrP amyloid RNAs Hybridization on gels and in Reduced mRNA in some cells; situ; measurements of PrP and APP mRNA present mRNAs and enzymes acting in neurons on RNAs Genes Recombinant DNA Anonymous marker on technology chromosome 21 linked to familial AD; APP gene localized to chromosome 21 ABBREVIATIONS AD Alzheimer's disease /A4 amyloid protein ChAT choline acetyltransferase CRF corticotropin-releasing factor GVD granulovacuolar degeneration kD kilodalton(s) mRNA messenger ribonucleic acid(s) NFT neurofibrillary tangle(s) PHF paired helical filament(s) PrP prion protein __________________________________________________________________________ *Source: DEMENTIA (Peter J. Whitehouse, Ed.), F.A. Davis Co., Philadelphia, 1993, Chapter 3, pp. 56-57.
In addition, a great many research studies and clinical investigations have been undertaken to study the structural deficiencies, chemical changes, and functional abnormalities both within the brain and within different populations of nerve cells. The depth of such investigations and studies are represented by the following publications: DEMENTIA (Peter J. Whitehouse, Ed.), F. A. Davis Company, Philadelphia. 1993; Paykel, et al., Arch. Gen. Psychiat. 51: 325-332 (1994); Amaducci, et al., Neurology, 36: 922-931 (1986); McKhann, et al., Neurology 34: 939-944 (1984); Heston et al., Arch. Gen. Psychiatry 38: 1085-1090 (1981); Aging of the Brain (Gispen and Traber, editors), Elsevier Science Publishers, Amsterdam, 1983, pages 275-282: Heyman et al., Ann. Neurol. 15: 335-341 (1984); Brayne C. and P. Calloway, Lancet 1: 1265-1267 (1988); Roth et al., Br. J. Psychiatry 149: 698-709 (1986); Medical Research Council, Report from the NRC Alzheimer's Disease Workshop, London, England, 1987; Morris et al., Neurology 41: 469-478 (1991); Aizheimer's Disease: Senile Dimentia and Related Disorders (Katzman, T. D. and R. L. Bick, editors), Raven Press, New York, 1994, pages 47-51; and the references cited within each of these publications.
In spite of the many research investigations and diverse studies undertaken to date, present clinical evaluations still cannot establish an unequivocal diagnosis of Alzheimer's Disease. To the contrary, the only presently known means for positively proving and demonstrating Alzheimer's Disease in a patient can only be achieved by a brain biopsy or a post-mortem examination to assess and determine the presence of neurofibrillary tangles (NFT) and senile (amyloid) plaques in brain tissue. These criteria for the definite diagnosis of Alzheimer's Disease are met only by histologic evidence.
Instead, a set of criteria for the diagnosis of probable Alzheimer's Disease have been described and include: (1) the presence of a dementia syndrome with defects in two or more areas of cognition; (2) progressive worsening of memory and other cognitive function over time; (3) a relatively intact level of consciousness; (4) age at disease onset at a time between 40 and 90 years of age; and (5) the specific absence of any other systemic or central nervous system process that could account for the progressive cognitive deterioration in the individual.
In addition, the probability of an accurate diagnosis in the living patient is augmented by laboratory examinations (such as VDRL and TFT) and by imaging studies (such as computed tomography and magnetic resonance imaging). Such laboratory examinations and/or imaging studies demonstrate the existence and effects of other causes of dementia (such as subdural hematoma, intracranial tumors, infection and brain infarction) and disclose results which are consistent with but are not themselves diagnostic of Alzheimer's Disease. Nevertheless, present clinical diagnoses are wrong in as many as 45% of cases. Thus, there is no sound basis or reliable test methodology at all today for the diagnosis of definite Aizheimer's Disease other than the microscopic examination of histologic material from brain biopsy or autopsy material. Instead, the best clinical diagnosis available to date is only a presumptive determination based on criteria which are evaluations of cognitive and neurological functions for that patient.
It is therefore overwhelmingly clear that there has been and remains today a long standing need for an accurate method to diagnose Alzheimer's Disease clinically in a living human subject with substantial certainty and reliability. In addition, were such a diagnostic methodology also able to be non-invasive, rapid in time required for performance, and precise via the accumulation of large quantities of empirical data, such a diagnostic methodology would be recognized by physicians and laymen alike as being a major advance and substantial improvement in this field.
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