Journal
ARCHIVES OF GENERAL PSYCHIATRY
Volume 69, Issue 1, Pages 98-106Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/archgenpsychiatry.2011.155
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Funding
- Swedish Research Council
- Swedish Brain Power
- ALF
- Johan and Jacob Soderberg Foundation
- Swedish Alzheimer Foundation
- Wachtmeister Foundation
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Context: Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease. Objectives: To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and beta-amyloid 1-42 (A beta 42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD. Design: A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years). Setting: Memory disorder clinic. Patients: A total of 137 patients with MCI who underwent lumbar puncture at baseline. Main Outcome Measure: Conversion to AD dementia. Results: During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF A beta 42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P<.001). Baseline CSF A beta 42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline A beta 42: P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%. Conclusions: Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of A beta 42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered A beta metabolism precedes tau-related pathology and neuronal degeneration.
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