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Original Article
Jan 2012

Cerebrospinal Fluid Levels ofβ-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia

Author Affiliations

Author Affiliations: Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö (Drs Buchhave, Minthon, Wallin, and Hansson); Neuropsychiatric Clinic, Skåne University Hospital, Malmö (Drs Buchhave, Minthon, Wallin, and Hansson); and Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal (Drs Zetterberg and Blennow), Sweden.

Arch Gen Psychiatry. 2012;69(1):98-106. doi:10.1001/archgenpsychiatry.2011.155
Abstract

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), andβ-amyloid 1-42 (Aβ42) 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 Aβ42 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 Aβ42 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 Aβ42: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 Aβ42 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 Aβ metabolism precedes tau-related pathology and neuronal degeneration.

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