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4 with late-onset familial and sporadic Alzheimer's disease
Departments of Medicine [Neurology] (Drs. Saunders, Strittmatter, Schmechel, Pericak-Vance, Alberts, and Roses, and S. Joo and B. Rosi), Neurobiology (Drs. Strittmatter, Schmechel, and Roses), and Pathology (Drs. Hulette and Crain), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC; the Department of Medicine [Neurology] (Drs. St. George-Hyslop and Crapper-MacLachlan), Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; the Department of Neurology (Dr. Gusella), Massachusetts General Hospital, Boston, MA, and the Department of Psychiatry (Dr. Goldgaber), State University of New York at Stony Brook, Stony Brook, NY.
Apolipoprotein E, type 
4 allele (APOE 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid ß-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE 4 is significantly associated with a series of probable sporadic AD patients (0.36 ± 0.042, AD, versus 0.16 ± 0.027, controls [allele frequency estimate ± standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE 4 allele (0.40 ± 0.026, p 
0.00001). These data support the involvement of ApoE 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of ß-peptide, and APOE 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
Address correspondence and reprint requests to Dr. Allen D. Roses, Box 2900, Duke University Medical Center, Durham, NC 27710
Supported by NIA LEAD Award AG-07922, NIA Alzheimer's Disease Center AG-05128 to A.D.R.; NIH General Clinical Research Centers Program M01-RR-30, and NINDS Center for Neurogenetic Diseases NS26330 to M.A.P.-V.; and NIA Center for Aging AG-09463 (Harvey J. Cohen, principal investigator), the Medical Research Council of Canada, the Alzheimer's Disease and Related Disorders Association, the Alzheimer's Association of Ontario, the American Health Assistance Foundation, and numerous contributions, less than $100, to the Joseph and Kathleen Bryan Alzheimer's Disease Research Center.
Received December 11, 1992. Accepted for publication in final form February 8, 1993.
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S. Ye, Y. Huang, K. Mullendorff, L. Dong, G. Giedt, E. C. Meng, F. E. Cohen, I. D. Kuntz, K. H. Weisgraber, and R. W. Mahley Apolipoprotein (apo) E4 enhances amyloid {beta} peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target PNAS, December 20, 2005; 102(51): 18700 - 18705. [Abstract] [Full Text] [PDF]
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E. J. Heyer, D. A. Wilson, D. H. Sahlein, J. Mocco, S. C. Williams, R. Sciacca, A. Rampersad, R. J. Komotar, J. Zurica, A. Benvenisty, et al. APOE-{varepsilon}4 predisposes to cognitive dysfunction following uncomplicated carotid endarterectomy Neurology, December 13, 2005; 65(11): 1759 - 1763. [Abstract] [Full Text] [PDF]
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G. Ramaswamy, Q. Xu, Y. Huang, and K. H. Weisgraber Effect of Domain Interaction on Apolipoprotein E Levels in Mouse Brain J. Neurosci., November 16, 2005; 25(46): 10658 - 10663. [Abstract] [Full Text] [PDF]
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R. N. Rosenberg Translational Research on the Way to Effective Therapy for Alzheimer Disease Arch Gen Psychiatry, November 1, 2005; 62(11): 1186 - 1192. [Abstract] [Full Text] [PDF]
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G. Li, J. B. Shofer, W. A. Kukull, E. R. Peskind, D. W. Tsuang, J.C.S. Breitner, W. McCormick, J. D. Bowen, L. Teri, G. D. Schellenberg, et al. Serum cholesterol and risk of Alzheimer disease: A community-based cohort study Neurology, October 11, 2005; 65(7): 1045 - 1050. [Abstract] [Full Text] [PDF]
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M. Faham, J. Zheng, M. Moorhead, H. Fakhrai-Rad, E. Namsaraev, K. Wong, Z. Wang, S. G. Chow, L. Lee, K. Suyenaga, et al. Multiplexed variation scanning for 1,000 amplicons in hundreds of patients using mismatch repair detection (MRD) on tag arrays PNAS, October 11, 2005; 102(41): 14717 - 14722. [Abstract] [Full Text] [PDF]
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Y. Nagasaka, K. Dillner, H. Ebise, R. Teramoto, H. Nakagawa, L. Lilius, K. Axelman, C. Forsell, A. Ito, B. Winblad, et al. A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings PNAS, October 11, 2005; 102(41): 14854 - 14859. [Abstract] [Full Text] [PDF]
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D. M. Hatters, M. S. Budamagunta, J. C. Voss, and K. H. Weisgraber Modulation of Apolipoprotein E Structure by Domain Interaction: DIFFERENCES IN LIPID-BOUND AND LIPID-FREE FORMS J. Biol. Chem., October 7, 2005; 280(40): 34288 - 34295. [Abstract] [Full Text] [PDF]
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E R Martin, P G Bronson, Y-J Li, N Wall, R-H Chung, D E Schmechel, G Small, P-T Xu, J Bartlett, N Schnetz-Boutaud, et al. Interaction between the {alpha}-T catenin gene (VR22) and APOE in Alzheimer's disease J. Med. Genet., October 1, 2005; 42(10): 787 - 792. [Abstract] [Full Text] [PDF]
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C. Paisan-Ruiz, A. E. Lang, T. Kawarai, C. Sato, S. Salehi-Rad, G. K. Fisman, T. Al-Khairallah, P. St George-Hyslop, A. Singleton, and E. Rogaeva LRRK2 gene in Parkinson disease: Mutation analysis and case control association study Neurology, September 13, 2005; 65(5): 696 - 700. [Abstract] [Full Text] [PDF]
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M. Moonis, J. M. Swearer, M. P. E. Dayaw, P. St. George-Hyslop, E. Rogaeva, T. Kawarai, and D. A. Pollen Familial Alzheimer disease: Decreases in CSF A{beta}42 levels precede cognitive decline Neurology, July 26, 2005; 65(2): 323 - 325. [Abstract] [Full Text] [PDF]
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D. M. Hatters, C. A. Peters-Libeu, and K. H. Weisgraber Engineering Conformational Destabilization into Mouse Apolipoprotein E: A MODEL FOR A UNIQUE PROPERTY OF HUMAN APOLIPOPROTEIN E4 J. Biol. Chem., July 15, 2005; 280(28): 26477 - 26482. [Abstract] [Full Text] [PDF]
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C. D. Hanning Postoperative cognitive dysfunction Br. J. Anaesth., July 1, 2005; 95(1): 82 - 87. [Full Text] [PDF]
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H. P. Grocott, H. M. Homi, and F. Puskas Cognitive Dysfunction After Cardiac Surgery: Revisiting Etiology Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2005; 9(2): 123 - 129. [Abstract] [PDF]
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D. R. Williams, R. de Silva, D. C. Paviour, A. Pittman, H. C. Watt, L. Kilford, J. L. Holton, T. Revesz, and A. J. Lees Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism Brain, June 1, 2005; 128(6): 1247 - 1258. [Abstract] [Full Text] [PDF]
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M. M. M. Wilhelmus, I. Otte-Holler, J. Davis, W. E. Van Nostrand, R. M. W. de Waal, and M. M. Verbeek Apolipoprotein E Genotype Regulates Amyloid-{beta} Cytotoxicity J. Neurosci., April 6, 2005; 25(14): 3621 - 3627. [Abstract] [Full Text] [PDF]
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M. S. Beeri, J. M. Silverman, K. L. Davis, D. Marin, H. Z. Grossman, J. Schmeidler, D. P. Purohit, D. P. Perl, M. Davidson, R. C. Mohs, et al. Type 2 Diabetes Is Negatively Associated With Alzheimer's Disease Neuropathology J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2005; 60(4): 471 - 475. [Abstract] [Full Text] [PDF]
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L. Bertram, M. Hiltunen, M. Parkinson, M. Ingelsson, C. Lange, K. Ramasamy, K. Mullin, R. Menon, A. J. Sampson, M. Y. Hsiao, et al. Family-Based Association between Alzheimer's Disease and Variants in UBQLN1 N. Engl. J. Med., March 3, 2005; 352(9): 884 - 894. [Abstract] [Full Text] [PDF]
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 T. E. Seeman, M.-H. Huang, P. Bretsky, E. Crimmins, L. Launer, and J. M. Guralnik Education and APOE-e4 in Longitudinal Cognitive Decline: MacArthur Studies of Successful Aging J. Gerontol. B. Psychol. Sci. Soc. Sci., March 1, 2005; 60(2): P74 - P83. [Abstract] [Full Text] [PDF]
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M. W. Bondi, W. S. Houston, L. T. Eyler, and G. G. Brown fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease Neurology, February 8, 2005; 64(3): 501 - 508. [Abstract] [Full Text] [PDF]
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N. Pomara, L. Willoughby, K. Wesnes, D. J. Greenblatt, and J. J. Sidtis Apolipoprotein E {varepsilon}4 Allele and Lorazepam Effects on Memory in High-Functioning Older Adults Arch Gen Psychiatry, February 1, 2005; 62(2): 209 - 216. [Abstract] [Full Text] [PDF]
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 L. N. Johnson-Anuna, G. P. Eckert, J. H. Keller, U. Igbavboa, C. Franke, T. Fechner, M. Schubert-Zsilavecz, M. Karas, W. E. Muller, and W. G. Wood Chronic Administration of Statins Alters Multiple Gene Expression Patterns in Mouse Cerebral Cortex J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 786 - 793. [Abstract] [Full Text] [PDF]
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A. Olsson, H. Vanderstichele, N. Andreasen, G. De Meyer, A. Wallin, B. Holmberg, L. Rosengren, E. Vanmechelen, and K. Blennow Simultaneous Measurement of {beta}-Amyloid(1-42), Total Tau, and Phosphorylated Tau (Thr181) in Cerebrospinal Fluid by the xMAP Technology Clin. Chem., February 1, 2005; 51(2): 336 - 345. [Abstract] [Full Text] [PDF]
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J.-C. Dodart, R. A. Marr, M. Koistinaho, B. M. Gregersen, S. Malkani, I. M. Verma, and S. M. Paul Gene delivery of human apolipoprotein E alters brain A{beta} burden in a mouse model of Alzheimer's disease PNAS, January 25, 2005; 102(4): 1211 - 1216. [Abstract] [Full Text] [PDF]
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Z. Zhou, A. Hoke, D. R. Cornblath, J. W. Griffin, and M. Polydefkis APOE {epsilon}4 is not a susceptibility gene in idiopathic or diabetic sensory neuropathy Neurology, January 11, 2005; 64(1): 139 - 141. [Abstract] [Full Text] [PDF]
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D. C. Steffens, K. A. Welsh-Bohmer, J. R. Burke, B. L. Plassman, J. L. Beyer, K. R. Gersing, and G. G. Potter Methodology and Preliminary Results From the Neurocognitive Outcomes of Depression in the Elderly Study J Geriatr Psychiatry Neurol, December 1, 2004; 17(4): 202 - 211. [Abstract] [PDF]
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