This invention relates to the diagnosis of Alzheimer Disease in human patients. The invention further relates to assessing the predisposition of a presymptomatic individual to develop the disease. More particularly, the present invention concerns the use of nucleic acid probes to detect gene alterations relating to Alzheimer Disease.
Alzheimer Disease is a progressive, degenerative disease of the central nervous system, characterized by specific neuropathological lesions. Many neuronal perikarya contain accumulations of neurofibrillary tangles (NFT), which are composed of paired helical filaments (PHF). Neurofibrillary tangles contain a protein structurally different from the amyloid found in extracellular aggregates in amyloid plaque cores and in cerebrovascular lesions of congophilic angiopathy. Similar amyloid lesions occur in such pathological conditions as Down Syndrome, Gerstmann-Straeussler-Scheinker Syndrome, Kuru, and in a minority of patients with Creutzfeldt-Jakob Disease.
A genetic component is indicated by large scale studies of pedigrees in which ten or more members of four generations have developed a dementia of the Alzheimer type before they were 70 years old. In such cases, it appears that an aberrant gene is transmitted as autosomal dominant. Most cases of Alzheimer Disease occur in people over 80 years of age, and it has been calculated that up to 30% of the Caucasian population over the age of 85 has the disease.
It is estimated that Alzheimer Disease currently affects over 2 million elderly people in the U.S. Because the disorder is usually late onset, the number of affected individuals will continue to grow as the elderly population increases in size. There are currently more than 25 million people in the U.S. over the age of 65, and this number will more than double by the year 2025.
One of the major biochemical symptoms in the cerebral cortex of Alzheimer patients is the appearance in plaque and blood vessel deposits of a protein known as the amyloid plaque core (APC) protein. This protein is an insoluble, highly aggregating, small polypeptide of relative molecular mass 4,500. APC has been understood to have 40-42 amino acids, and is currently believed more likely to be 40 amino acids in length. This polypeptide is also deposited in the brains of relatively older individuals with trisomy 21 (Down
Syndrome). Kang et al, Nature 325, 733-736, 1987, propose that the amyloid protein is of neuronal origin and is part of a larger precursor protein. To identify this precusor, a full-length complementary DNA clone coding for the APC protein was isolated and sequenced. The predicted precursor consists of 695 residues and contains features characteristic of glycosylated cell-surface receptors. This cDNA sequence, together with the localization of its gene in chromosome 21, suggests that the cerebral amyloid deposited in Alzheimer Disease and aged Down Syndrome is caused either by aberrant catabolism of a cell-surface receptor, or by aberrant synthesis or processing of its mRNA. In order to determine patterns of expression of the gene in brain, APC cDNA was hybridized to tissue sections of the mouse nervous system. Amyloid precursor protein mRNA was detected in most neurons of the central and peripheral nervous system.
A means for early and accurate diagnosis of Alzheimer Disease will have a major impact on the progress of research on dementia. Because no peripheral biochemical marker for Alzheimer Disease has been found, a definitive diagnosis of the disorder can be made only if histologic confirmation is obtained by performance of a cerebral biopsy or an autopsy. Despite the fact that Alzheimer Disease is essentially an untreatable condition, there would be significant value to know whether or not an individual with Alzheimer symptoms in fact has the disease. A number of treatable conditions are characterized by symptoms similar to those found in patients with Alzheimer Disease. Some such treatable conditions are brain tumors, thyroid and other endocrine dysfunctions, depression, infection, vitamin and mineral deficiencies, metabolic disorders, unrecognized injuries, and side effects of medication. The medical literature advises physicians to conduct a thorough examination, medical history, and testing in order to rule out reversible disorders before diagnosing the untreatable Alzheimer condition.