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Previous Volume 338:506-511 February 19, 1998 Number 8 Next

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ABSTRACT

Background The 4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimer's disease, but its value in the diagnosis remains uncertain.

Methods We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimer's disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE 4 allele were calculated, with pathologically confirmed Alzheimer's disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate.

Results Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimer's disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimer's disease, as compared with 65 percent of those with pathologically confirmed Alzheimer's disease, had at least one APOE 4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE 4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimer's disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center.

Conclusions APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimer's disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.

Source Information

From the Gertrude H. Sergievsky Center (R.M., M.-X.T.), the Taub Alzheimer's Disease Research Center (R.M., M.-X.T.), and the Department of Medicine (S.S.), Columbia University College of Physicians and Surgeons, New York; Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, N.C. (A.M.S., A.D.R.); Emory Alzheimer's Disease Research Center, Emory University and Veterans Affairs Medical Center, Atlanta (S.M.); Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, Chicago (D.E.); the Department of Neurology, Harvard Medical School, Boston (B.T.H.); the Department of Pathology, Johns Hopkins Medical School, Baltimore (B.C.); and the National Institute on Aging, Bethesda, Md. (C.H.P.).

Address reprint requests to Dr. Mayeux at the Gertrude H. Sergievsky Center, 630 W. 168th St., New York, NY 10032.

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• McPherson, E. (2006). Genetic diagnosis and testing in clinical practice.. Clin Med Res 4: 123-129 [Abstract] [Full Text]  
• Huang, X., Chen, P., Kaufer, D. I., Troster, A. I., Poole, C. (2006). Apolipoprotein E and Dementia in Parkinson Disease: A Meta-analysis. Arch Neurol 63: 189-193 [Abstract] [Full Text]  
• Jarvik, L. F., Blazer, D. (2005). Children of Alzheimer Patients: An Overview. J Geriatr Psychiatry Neurol 18: 181-186  
• van der Flier, W M, Scheltens, P (2005). Use of laboratory and imaging investigations in dementia. J. Neurol. Neurosurg. Psychiatry 76: v45-v52 [Full Text]  
• Luchsinger, J. A., Reitz, C., Honig, L. S., Tang, M. X., Shea, S., Mayeux, R. (2005). Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65: 545-551 [Abstract] [Full Text]  
• Devanand, D. P., Pelton, G. H., Zamora, D., Liu, X., Tabert, M. H., Goodkind, M., Scarmeas, N., Braun, I., Stern, Y., Mayeux, R. (2005). Predictive Utility of Apolipoprotein E Genotype for Alzheimer Disease in Outpatients With Mild Cognitive Impairment. Arch Neurol 62: 975-980 [Abstract] [Full Text]  
• Vandenberghe, R, Tournoy, J (2005). Cognitive aging and Alzheimer's disease. Postgrad. Med. J. 81: 343-352 [Abstract] [Full Text]  
• Wright, A F (2005). Neurogenetics II: complex disorders. J. Neurol. Neurosurg. Psychiatry 76: 623-631 [Abstract] [Full Text]  
• Yue, L., Rasouli, N., Ranganathan, G., Kern, P. A., Mazzone, T. (2004). Divergent Effects of Peroxisome Proliferator-activated Receptor {gamma} Agonists and Tumor Necrosis Factor {alpha} on Adipocyte ApoE Expression. J. Biol. Chem. 279: 47626-47632 [Abstract] [Full Text]  
• Silverman, D. H.S. (2004). Brain 18F-FDG PET in the Diagnosis of Neurodegenerative Dementias: Comparison with Perfusion SPECT and with Clinical Evaluations Lacking Nuclear Imaging. JNM 45: 594-607 [Abstract] [Full Text]  
• Devi, G., Williamson, J., Massoud, F., Anderson, K., Stern, Y., Devanand, D. P., Mayeux, R. (2004). A Comparison of Family History of Psychiatric Disorders Among Patients With Early- and Late-Onset Alzheimer's Disease. J. Neuropsychiatry Clin. Neurosi. 16: 57-62 [Abstract] [Full Text]  
• Knopman, D. S., Boeve, B. F., Petersen, R. C. (2003). Essentials of the Proper Diagnoses of Mild Cognitive Impairment, Dementia, and Major Subtypes of Dementia. Mayo Clin Proc. 78: 1290-1308 [Abstract]  
• Clark, C. M., Karlawish, J. H.T. (2003). Alzheimer Disease: Current Concepts and Emerging Diagnostic and Therapeutic Strategies. ANN INTERN MED 138: 400-410 [Abstract] [Full Text]  
• Petrella, J. R., Coleman, R. E., Doraiswamy, P. M. (2003). Neuroimaging and Early Diagnosis of Alzheimer Disease: A Look to the Future. Radiology 226: 315-336 [Abstract] [Full Text]  
• Tsuboi, Y., Josephs, K. A., Cookson, N., Dickson, D. W. (2003). APOE E4 is a determinant for Alzheimer type pathology in progressive supranuclear palsy. Neurology 60: 240-245 [Abstract] [Full Text]  
• Bossuyt, P. M., Reitsma, J. B., Bruns, D. E., Gatsonis, C. A., Glasziou, P. P., Irwig, L. M., Moher, D., Rennie, D., de Vet, H. C.W., Lijmer, J. G. (2003). The STARD Statement for Reporting Studies of Diagnostic Accuracy: Explanation and Elaboration. ANN INTERN MED 138: W1-W12 [Abstract] [Full Text]  
• Bossuyt, P. M., Reitsma, J. B., Bruns, D. E., Gatsonis, C. A., Glasziou, P. P., Irwig, L. M., Moher, D., Rennie, D., de Vet, H. C.W., Lijmer, J. G. (2003). The STARD Statement for Reporting Studies of Diagnostic Accuracy: Explanation and Elaboration. Clin. Chem. 49: 7-18 [Abstract] [Full Text]  
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• Greicius, M D, Geschwind, M D, Miller, B L (2002). Presenile dementia syndromes: an update on taxonomy and diagnosis. J. Neurol. Neurosurg. Psychiatry 72: 691-700 [Abstract] [Full Text]  
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• Neumann, P. J., Hammitt, J. K., Mueller, C., Fillit, H. M., Hill, J., Tetteh, N. A., Kosik, K. S. (2001). Public Attitudes About Genetic Testing For Alzheimer's Disease. Health Aff (Millwood) 20: 252-264 [Abstract] [Full Text]  
• Knopman, D. S., DeKosky, S. T., Cummings, J. L., Chui, H., Corey-Bloom, J., Relkin, N., Small, G. W., Miller, B., Stevens, J. C. (2001). Practice parameter: Diagnosis of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56: 1143-1153 [Abstract] [Full Text]  
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• , S. (2001). Recent advances: Geriatric. BMJ 322: 86-89 [Full Text]  
• LIDDELL, M. B., LOVESTONE, S., OWEN, M. J. (2001). Genetic risk of Alzheimer's disease: advising relatives. Br. J. Psychiatry 178: 7-11 [Abstract] [Full Text]  
• Bigler, E. D., Lowry, C. M., Anderson, C. V., Johnson, S. C., Terry, J., Steed, M. (2000). Dementia, Quantitative Neuroimaging, and Apolipoprotein E Genotype. Am. J. Neuroradiol. 21: 1857-1868 [Abstract] [Full Text]  
• Plassman, B. L., Havlik, R. J., Steffens, D. C., Helms, M. J., Newman, T. N., Drosdick, D., Phillips, C., Gau, B. A., Welsh-Bohmer, K. A., Burke, J. R., Guralnik, J. M., Breitner, J. C. S. (2000). Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology 55: 1158-1166 [Abstract] [Full Text]  
• Albert, M. S., Drachman, D. A. (2000). Alzheimer's disease: What is it, how many people have it, and why do we need to know?. Neurology 55: 166-168 [Full Text]  
• Ganguli, M., Chandra, V., Kamboh, M. I., Johnston, J. M., Dodge, H. H., Thelma, B. K., Juyal, R. C., Pandav, R., Belle, S. H., DeKosky, S. T. (2000). Apolipoprotein E Polymorphism and Alzheimer Disease: The Indo-US Cross-National Dementia Study. Arch Neurol 57: 824-830 [Abstract] [Full Text]  
• Riley, K. P., Snowdon, D. A., Saunders, A. M., Roses, A. D., Mortimer, J. A., Nanayakkara, N. (2000). Cognitive Function and Apolipoprotein E in Very Old Adults: Findings From the Nun Study. Journals of Gerontology Series B: Psychological Sciences and Social Science 55: 69S-75 [Abstract] [Full Text]  
• Steffens, D. C., Plassman, B. L., Helms, M. J., Welsh-Bohmer, K. A., Newman, T. T., Breitner, J. C. S. (2000). APOE and AD concordance in twin pairs as predictors of AD in first-degree relatives. Neurology 54: 593-593 [Abstract] [Full Text]  
• O'Donnell, H. C., Rosand, J., Knudsen, K. A., Furie, K. L., Segal, A. Z., Chiu, R. I., Ikeda, D., Greenberg, S. M. (2000). Apolipoprotein E Genotype and the Risk of Recurrent Lobar Intracerebral Hemorrhage. NEJM 342: 240-245 [Abstract] [Full Text]  
• Sacco, R. L. (2000). Lobar Intracerebral Hemorrhage. NEJM 342: 276-279 [Full Text]  
• Prince, M., Lovestone, S., Cervilla, J., Joels, S., Powell, J., Russ, C., Mann, A. (2000). The association between APOE and dementia does not seem to be mediated by vascular factors. Neurology 54: 397-397 [Abstract] [Full Text]  
• Sousa, M. M., Berglund, L., Saraiva, M. J. (2000). Transthyretin in high density lipoproteins: association with apolipoprotein A-I. J. Lipid Res. 41: 58-65 [Abstract] [Full Text]  
• Munoz, D. G., Feldman, H. (2000). Causes of Alzheimer's disease. CMAJ 162: 65-72 [Abstract] [Full Text]  
• Greenberg, S. M., Tennis, M. K., Brown, L. B., Gomez-Isla, T., Hayden, D. L., Schoenfeld, D. A., Walsh, K. L., Corwin, C., Daffner, K. R., Friedman, P., Meadows, M.-E., Sperling, R. A., Growdon, J. H. (2000). Donepezil Therapy in Clinical Practice: A Randomized Crossover Study. Arch Neurol 57: 94-99 [Abstract] [Full Text]  
• Alvarez, R., Alvarez, V., Lahoz, C. H, Martinez, C., Pena, J., Sanchez, J. M, Guisasola, L. M, Salas-Puig, J., Moris, G., Vidal, J. A, Ribacoba, R., Menes, B. B, Uria, D., Coto, E. (1999). Angiotensin converting enzyme and endothelial nitric oxide synthase DNA polymorphisms and late onset Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 67: 733-736 [Abstract] [Full Text]  
• Tsuang, D., Larson, E. B., Bowen, J., McCormick, W., Teri, L., Nochlin, D., Leverenz, J. B., Peskind, E. R., Lim, A., Raskind, M. A., Thompson, M. L., Mirra, S. S., Gearing, M., Schellenberg, G. D., Kukull, W. (1999). The Utility of Apolipoprotein E Genotyping in the Diagnosis of Alzheimer Disease in a Community-Based Case Series. Arch Neurol 56: 1489-1495 [Abstract] [Full Text]  
• (1999). Goals and Objectives for Molecular Pathology Education in Residency Programs. J. Mol. Diagn. 1: 5-15 [Abstract] [Full Text]  
• Massoud, F., Devi, G., Stern, Y., Lawton, A., Goldman, J. E., Liu, Y., Chin, S. S., Mayeux, R. (1999). A Clinicopathological Comparison of Community-Based and Clinic-Based Cohorts of Patients With Dementia. Arch Neurol 56: 1368-1373 [Abstract] [Full Text]  
• Andreasen, N., Minthon, L., Clarberg, A., Davidsson, P., Gottfries, J., Vanmechelen, E., Vanderstichele, H., Winblad, B., Blennow, K. (1999). Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample. Neurology 53: 1488-1488 [Abstract] [Full Text]  
• Hegele, R. A., Merz, J. F., Silverman, L. M. (1999). Uncovering Rare Mutations: An Unforeseen Complication of Routine Genotyping of APOE • J. Merz and L. Silverman provide the following comment:. Clin. Chem. 45: 1579-1581 [Full Text]  
• Richards, S. S., Hendrie, H. C. (1999). Diagnosis, Management, and Treatment of Alzheimer Disease: A Guide for the Internist. Arch Intern Med 159: 789-798 [Abstract] [Full Text]  
• Drachman, D. A., Newell, K. L. (1999). Case 12-1999- A 67-Year-Old Man with Three Years of Dementia. NEJM 340: 1269-1277 [Full Text]  
• Growdon, J. H. (1999). Biomarkers of Alzheimer Disease. Arch Neurol 56: 281-283 [Abstract] [Full Text]  
• Barker, W., Harwood, D., Duara, R., Mullan, M., Fallin, D., St. George Hyslop, P., Rogaeva, E., Song, Y., Farkas, B. L., Grant, W. B., Mendez, H. A., Tang, M.-X., Mayeux, R. (1998). The APOE-{epsilon}4 Allele and Alzheimer Disease Among African Americans, Hispanics, and Whites. JAMA 280: 1661-1663 [Full Text]  
• Price, D. L., Sisodia, S. S., Borchelt, D. R. (1998). Genetic Neurodegenerative Diseases: The Human Illness and Transgenic Models. Science 282: 1079-1083 [Abstract] [Full Text]  
• Growdon, J. H. (1998). Apolipoprotein E and Alzheimer Disease. Arch Neurol 55: 1053-1054 [Full Text]