Appearance
Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease.
Literature Information
| DOI | 10.1056/NEJM199802193380804 |
|---|---|
| PMID | 9468467 |
| Journal | The New England journal of medicine |
| Impact Factor | 78.5 |
| JCR Quartile | Q1 |
| Publication Year | 1998 |
| Times Cited | 127 |
| Keywords | Apolipoprotein E genotype, Alzheimer's disease, diagnostic specificity |
| Literature Type | Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S. |
| ISSN | 0028-4793 |
| Pages | 506-11 |
| Issue | 338(8) |
| Authors | R Mayeux, A M Saunders, S Shea, S Mirra, D Evans, A D Roses, B T Hyman, B Crain, M X Tang, C H Phelps |
TL;DR
This study evaluates the diagnostic value of the APOE epsilon4 allele in Alzheimer's disease by comparing clinical diagnoses with autopsy-confirmed cases in 2,188 patients. While the APOE genotype alone shows inadequate sensitivity and specificity for diagnosis, its inclusion alongside clinical criteria significantly enhances specificity, underscoring its potential role in refining Alzheimer's disease diagnosis.
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Apolipoprotein E genotype · Alzheimer's disease · diagnostic specificity
Abstract
BACKGROUND The epsilon4 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 epsilon4 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 epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 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.
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Primary Questions Addressed
- How does the presence of the APOE epsilon4 allele influence the progression of Alzheimer's disease in diagnosed patients?
- What are the implications of using APOE genotyping in early diagnosis versus late-stage diagnosis of Alzheimer's disease?
- How do other genetic factors compare to APOE epsilon4 in their association with Alzheimer's disease diagnosis and prognosis?
- What alternative biomarkers or diagnostic tools are currently being researched to improve the sensitivity and specificity of Alzheimer's disease diagnosis?
- How do demographic factors, such as age and sex, interact with the diagnostic utility of APOE genotyping in Alzheimer's disease?
Key Findings
1. Research Background and Objective
The study investigates the role of the apolipoprotein E (APOE) genotype, particularly the epsilon4 allele, in the diagnosis of Alzheimer's disease (AD). The epsilon4 allele has been established as a significant genetic risk factor for Alzheimer's; however, its utility as a standalone diagnostic tool remains ambiguous. The research aims to evaluate the sensitivity and specificity of the APOE epsilon4 genotype in diagnosing Alzheimer's disease compared to clinical diagnoses and autopsy-confirmed cases.
2. Main Methods and Findings
The research involved a comprehensive review of clinical and autopsy diagnoses from 2,188 patients referred to 26 Alzheimer's disease centers for dementia evaluation. The study calculated the sensitivity and specificity of both clinical diagnoses and the presence of the APOE epsilon4 allele, using pathologically confirmed Alzheimer's disease as the benchmark. Key findings indicate:
- Out of 2,188 patients, 1,833 received a clinical diagnosis of Alzheimer's, which was pathologically confirmed in 1,770 cases.
- Among those clinically diagnosed, 62% had at least one APOE epsilon4 allele, compared to 65% of those with confirmed Alzheimer's.
- The clinical diagnosis exhibited a sensitivity of 93% and a specificity of 55%. In contrast, the APOE epsilon4 allele had a sensitivity of 65% and specificity of 68%.
- Importantly, integrating APOE genotype information increased the overall specificity to 84% for patients meeting clinical criteria, though this came with a decrease in sensitivity. This improvement in specificity remained statistically significant even after adjusting for age, clinical diagnosis, sex, and center differences.
3. Core Conclusion
The study concludes that while APOE genotyping provides neither adequate sensitivity nor specificity to function as a standalone diagnostic test for Alzheimer's disease, its incorporation alongside clinical diagnostic criteria significantly enhances diagnostic specificity. This dual approach can aid in more accurate identification of Alzheimer's disease in patients.
4. Research Significance and Impact
This research highlights the complexities of diagnosing Alzheimer's disease and the necessity of combining genetic insights with clinical assessments. The findings suggest that APOE genotyping should not be used in isolation but rather as a complementary tool in the diagnostic process. The enhancement of diagnostic specificity could lead to improved patient management and care strategies, potentially guiding therapeutic decisions and better informing patients and families about prognosis. This study contributes to the ongoing discourse on the integration of genetic testing in clinical practice, emphasizing the importance of holistic approaches in Alzheimer's disease diagnosis.
Literatures Citing This Work
- The burden of dementia. A medical and research perspective. - P Antuono;J Beyer - Theoretical medicine and bioethics (1999)
- Angiotensin converting enzyme and endothelial nitric oxide synthase DNA polymorphisms and late onset Alzheimer's disease. - R Alvarez;V Alvarez;C H Lahoz;C Martínez;J Peña;J M Sánchez;L M Guisasola;J Salas-Puig;G Morís;J A Vidal;R Ribacoba;B B Menes;D Uría;E Coto - Journal of neurology, neurosurgery, and psychiatry (1999)
- Dementia, quantitative neuroimaging, and apolipoprotein E genotype. - E D Bigler;C M Lowry;C V Anderson;S C Johnson;J Terry;M Steed - AJNR. American journal of neuroradiology (2000)
- Sandwich ELISA for the measurement of Apo-E4 levels in serum and the estimation of the allelic status of Apo-E4 isoforms. - Y Uchida;S Ito;N Nukina - Journal of clinical laboratory analysis (2000)
- Geriatric medicine. - S E Straus - BMJ (Clinical research ed.) (2001)
- Causes of Alzheimer's disease. - D G Munoz;H Feldman - CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne (2000)
- Goals and objectives for molecular pathology education in residency programs. The Association for Molecular Pathology Training and Education Committee. - The Journal of molecular diagnostics : JMD (1999)
- Clinical significance of neurobiochemical profiles in the lumbar cerebrospinal fluid of Alzheimer's disease patients. - N Rösler;I Wichart;K A Jellinger - Journal of neural transmission (Vienna, Austria : 1996) (2001)
- Why should primary care physicians know about the genetics of dementia? - L E Pinsky;W Burke;T D Bird - The Western journal of medicine (2001)
- The apolipoprotein E gene, attention, and brain function. - Raja Parasuraman;Pamela M Greenwood;Trey Sunderland - Neuropsychology (2002)
... (117 more literatures)
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