Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1997-02-21
1999-08-10
Allen, Marianne P.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
514297, 536 2431, C07H 2104
Patent
active
059357819
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
(a) Field of the Invention
The invention relates to a method for the treatment of Alzheimer's disease in a patient based on the cholinergic activity in the brain.
(b) Description of Prior Art
Apolipoprotein E (apo E) functions as a ligand in the process of receptor mediated internalization of lipid-rich lipoproteins, and it is probably also involved in reverse lipid transport (Mahley R. W. et al., 1983, Biochem. Biophys. Acta. 737:197-222). In the central nervous system (CNS), apoE plays a central role in the mobilization and redistribution of cholesterol and phospholipid during membrane remodeling associated with synaptic plasticity (Poirier J. et al., 1991, Mol. Brain. Res., 9:191-195; Poirier J. et al., 1991, Mol. Brain. Res., 11:97-106; Poirier J. et al., 1993, Neuroscience, 55:81-90). The importance of apoE in the brain is further underscored by the absence of other key plasma apolipoproteins such as apo A1 and apo B (Roheim P. S. et al., 1979, Proc. Natl. Acad. Sci., 76:4646-4649) in this tissue. ApoE mRNA is found predominantly in astrocytes in the CNS.
The apoE gene on chromosome 19 has three common alleles (E2, E3, E4), which encode three major apoE isoforms. Recently, the frequency of the apoE4 allele was shown to be markedly increased in sporadic (Poirier J. et al., 1993, Apolipoprotein E phenotype and Alzheimer's Disease, Lancet, 342:697-699; Noguchi S. et al., 1993, Lancet (letter), 342:737) and late onset familial Alzheimer's disease (AD) (Corder E. H. et al., 1993, Science, 261:921-923; Payami H. et al., 1993, Lancet (letter), 342:738). A gene dosage effect was observed in both sporadic and familial cases (i.e. as age of onset increases, E4 allele copy number decreases). Women, who are generally at a greater risk of developing Alzheimer's disease, show increased E4 allele frequency when compared to age matched men.
Preliminary studies have shown that apoE mRNA levels are relatively unchanged (Poirier J. et al., 1991, In: Basic and therapeutic strategies in Alzheimer's and Parkinsons's diseases, T. Nagatsu, F. Abraham. eds., New York, Plenum Press, 191-194) in post-mortem brains of AD patients. These results were obtained from patients whose genotypes were undetermined.
It would be highly desirable to be provided with means to determine the cholinergic activity in the brain of Alzheimer's disease patients to determine if cholinomimetics-based therapies should be carried out.
SUMMARY OF THE INVENTION
One aim of the present invention is to provide with means to assess the cholinergic activity in the brain of Alzheimer's disease patients to determine if cholinomimetics-based therapies should be carried out.
In accordance with the present invention there is provided a method for the treatment of Alzheimer's disease in a genetically characterized Alzheimer's patient for its pre-disposition to respond to cholinomimetic therapies, which comprises: absence of apolipoprotein E4 allele from peripheral tissues of the patient which is indicative of the degree of impairment in brain acetylcholine synthesis and nicotinic receptor activity; and the degree of impairment of step a).
Therapeutic agents to be used in accordance with the present invention may be selected from the group consisting of inhibitors of acetylcholine degradation, inducers of acetylcholine synthesis, acetylcholine agonists or mimics, and muscarinic M2-receptor antagonists.
In accordance with the present invention there is also provided a method for the identification of human subjects with cognitive impairments due to age, Alzheimer's disease or other neurodegenerative diseases, to be responsive to cholinomimetic therapies, which comprises determining the number of copies of the apoE2 and apoE3 gene alleles or the absence of apoE4 gene allele in a biological sample of the patient directly by using appropriate apoE2 and apoE3 probes or indirectly by phenotyping, and wherein the presence of apoE2 and/or apoE3 gene alleles and the absence of apoE4 indicate a pre-disposition to respond to cholinomimetics-base
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Poirier et al., "In: Basic and Therapeutic Strategies in Alzheimer's and Parkinson's Diseases", Plenum Press 191-194, 1991.
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Allen Marianne P.
Bieker-Brady Kristina
McGill University
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