1.  Field of the Invention
The instant invention generally relates to the diagnosis and monitoring of Alzheimer's Disease. 
Alzheimer's Disease (AD) is the most common cause of progressive intellectual failure in aged humans, and is typified by gradual neurological deterioration including memory loss, disorientation, and general intellectual regression.  It eventually produces additional symptoms of physical deterioration, such as motor disability, incontinence and weight loss, and is often fatal.  It has been observed in races and ethnic groups worldwide and presents a present and future major public health and economic problem.  The disease is estimated to affect two to three million individuals in the United States alone. 
The problem is compounded by substantial difficulties in making a definitive diagnosis of the disease during the patient's lifetime.  Typically, Alzheimer's Disease is definitively diagnosed at autopsy, from an examination of the condition of the brain.  Alzheimer's Disease is earmarked by structural changes in the form of filamentous lesions occurring in particular regions of the brain.  These brain lesions are referred to as (1) senile (amyloid) plaques; (2) amyloid angiopathy (deposition of amyloid in small blood vessels); (3) neurofibrillary tangles; and (4) altered nerve cell fibers (neuritic dystrophy). 
2.  Background Art
The brains of virtually all very old humans contain at least some small quantities of the filamentous brain lesions which are characteristic of Alzheimer's Disease (AD) and occur within neurons (neurofibrillary tangles), in extracellular cerebral deposits (senile or amyloid plaques) and in meningeal and cerebral blood vessels (amyloid angiopathy).  Chemical, immunochemical and molecular biological analyses during recent years have shown that a 4.2 kiloDalton (kDa) protein (of about 38 to about 43 amino acids), designated .beta.-amyloid protein (.beta.-AP) or A4, is a subunit of the vascular and cerebral amyloid filaments that occur in the brains of individuals with AD or with trisomy 21 (Down's syndrome), as well as (to a lesser extent) in individuals undergoing the normal aging process.  See Glenner and Wong, Biochem.  Biophys.  Res.  Commun.  120: 885-890 (1984); Glenner and Wong, Biochem.  Biophys.  Res.  Commun.  122: 1131-1135 (1984); Masters et al.,  Proc.  Natl.  Acad.  Sci.  USA 82: 4245-4249 (1985); Selkoe et al.,  J. Neurochem.  46: 1820-1834 (1986); Kang et al.,  Nature 325: 733-736 (1987); and Coria et al.,  Am.  J. Pathol.  129: 422-428 (1988).  These analyses have also shown that the .beta.-AP is a small fragment of a much larger precursor protein that is normally produced by cells in many tissues of various animals.  The gene coding for this .beta.-AP precursor protein in humans is located on the long arm of human chromosome 21. 
The first purification and partial amino acid sequencing of the .beta.-amyloid protein of AD was reported by Glenner and Wong in 1984 (Glenner and Wong, Biochem.  Biophys.  Res.  Commun.  120: 885-890, (1984)).  They isolated .beta.-AP from the meningeal blood vessels of patients who died with AD, using a modification of a long-established protocol for purifying amyloids from tissues.  They were able to establish the amino acid sequence of the first 28 amino acids of what was later shown to be a 38-43 amino acid protein.  The isolation procedure that they used and their sequence data are described in U.S. Pat.  No.  4,666,829 issued to Glenner et al.  on May 19, 1987.  In 1985, they made synthetic peptides including the first 10 amino acids of the 28-amino acid sequence identified by them.  These synthetic peptides were then injected into either rabbits or mice to produce, respectively, polyclonal or monoclonal antibodies.  These antibodies detected (i.e., reacted with) both the senile (amyloid) plaques and the vascular amyloid deposits in AD and normal aged brains. 
PCT application having Int.  Pub.  No.  WO 88/03951 assigned to California Biotechnology, Inc., is directed to certain DNA sequences encoding the .beta.-amyloid precursor protein, and to the use of their recombinant proteins for generating antibodies for cerebrospinal fluid or serum diagnosis of Alzheimer's Disease. 
Throughout the more than 80 years since Alzheimer's Disease was first identified as a disease, the pathological lesions of AD have been found only in the brain.  Since the examination of a patient's brain tissue by biopsy is particularly invasive and, therefore, very rarely carried out, a need exists for an effective, less invasive diagnostic method that can be used simply and safely on a living subject.