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(12) United States Patent (10) Patent No.: US 6,342,350 B1 Tanzi Et Al USOO6342350B1 (12) United States Patent (10) Patent No.: US 6,342,350 B1 Tanzi et al. (45) Date of Patent: Jan. 29, 2002 (54) ALPHA-2-MACROGLOBULIN DIAGNOSTIC with Chinese late onset Alzheimer's Disease,” Neuroscience TEST Letters 269:173–177 (1999). Dodel, R.C., et al., “C-2 Macroglobulin and the Risk of (75) Inventors: Rudolph E. Tanzi, Hull; Bradley T. Alzheimer's Disease,” Neurology 54:438-442 (2000). Hyman, Swampscott; George W. Dow, D.J., et al., “C-2 Macroglobulin Polymorphism and Rebeck, Somerville; Deborah L. Alzheimer Disease risk in the UK,” Nature Genetics Blacker, Newton, all of MA (US) 22:16–17 (May 1999). (73) Assignee: The General Hospital Corporation, Du, Y., et al., “c-Macroglobulin Attenuates B-Amyloid Boston, MA (US) Peptide 1-40 Fibril Formation and Associated Neurotoxicity of Cultured Fetal Rat Cortical Neurons,” J. of Neurochem. 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C12O 1/68 morphism is not associated with Autopsy-confirmed late-onset Alzheimer Disease,” Neurosci. Lett. 273.61-63 (52) U.S. Cl. ........................................... 435/6; 435/91.2 (1999). Korovaitseva, G.I., et al., “Alpha-2 Macroglobulin Gene in (58) Field of Search .................. 435/6, 91.2; 536/24.33 early- and late-onset Alzheimer Disease, NeurOSci. Lett. 27.1:129-131 (1999). (56) References Cited Myllykangas, L., et al., “Genetic ASSociation of C-Macro U.S. PATENT DOCUMENTS globulin with Alzheimer's Disease in a Finnish Elderly Population.” Ann. of Neuro. 46(3):382–390 (1999). 5,508,167 A 4/1996 Roses et al. ................... 435/6 Rogaeva, E.A., et al., “An O-2 macroglobulin Insertion-De 5,716,828 A 2/1998 Roses et al. ................... 435/6 5,767,248 A 6/1998 Roses et al. ........... 530/388.25 letion Polymorphism in Alzheimer's Disease,” Nature 5.830,670 A 11/1998 De La Monte et al. ...... 435/7.2 Genetics 22:19-22 (May 1999). 5.948,634 A 10/1999 De La Monte et al. .... 435/69.1 Romas, S.N., et al., “The Deletion polymorphism and 5.948.888 A 10/1999 De La Monte et al. ..... 530/350 Val1000lle in O-2-macroglobulin and alzheimer Disease in 6,071,705 A 6/2000 Wands et al. ................ 435/7.1 Carribbean Hispanics.” Neurosci. Lett. 27.9:133-136 (2000). FOREIGN PATENT DOCUMENTS Rudrasingham, V., et al., "C-2 Macroglobulin Gene and Alzheimer Disease,” Nature Genetics 22:17-19 (May WO WO 91/03557 3/1991 WO WO 92/03474 3/1992 1999). WO WO 96/39834 12/1996 WO WO 99/11824 3/1999 (List continued on next page.) OTHER PUBLICATIONS Primary Examiner Lisa B. Arthur Nielsen, K.L., et al., “Identification of residues in C-mac (74) Attorney, Agent, or Firm-Sterne, Kessler, Goldstein roglobulins important for binding to the C-2-macroglobulin & Fox PL.L.C. receptor/low density lipoprotein receptor-related protein,” (57) ABSTRACT J. Biol. Chem. 27.1:12909–12912 (1996). Soto, C., et al., “B-Sheet breaker peptides inhibit fibrillo The disclosed invention relates to a diagnostic method for genesis in a rat brain model of amyloidosis: Implications for Alzheimer's disease based on genotyping the Alpha-2- Alzheimer's therapy,” Nature Med. 4:822–826 (1988). Macroglobulin locus. A Statistically significant correlation International Search Report for International Application was found between inheritance of particular alleles of the No. PCT/USOO/02412, mailed Jul. 6, 2000. Alpha-2-Macroglobulin gene and the occurrence of Alzhe “Freely Associating.” Nature Genetics 22:1-2 (May 1999). imer's disease. The diagnostic method involves the isolation Alvarez, V., et al., “ASSociation between an O2 Macroglo of nucleic acid from an individual and Subsequent genotyp bulin DNA Polymorphism and Late-Onset Alzheimer's Dis ing by means Such as Sequencing or restriction fragment ease,” Biochem. and BiophyS. Res. Comm. 264:48-50 length polymorphism analysis. The invention also provides (1999). a means of genotype analysis through protein isotyping Blacker, D., et al., “Correspondence,” Nature Genetics Alpha-2-Macroglobulin variant proteins. Finally, kits for 22:21–22 (May 1999). nucleic acid analysis or protein analysis are taught. 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