Use of Cerebrospinal Fluid Biomarkers for Diagnosis of Incipient Alzheimer Disease in Patients with Mild Cognitive Impairment

Abstract

Alzheimer disease (AD)1 is the most common cause of dementia. In the US, AD is the sixth leading cause of death in Americans aged 65 or older. In the US, AD affects an estimated 5.3 million people and is expected to afflict approximately 35 million people worldwide by 2010 (1). The global health economic impact of AD-related dementia is predicted to overwhelm social services in coming decades as a consequence of demographic aging. Definitive diagnosis of AD at postmortem examination of the brain reveals gross and microscopic evidence of neuronal atrophy and the presence of 2 histological hallmarks: amyloid β (Aβ)-containing plaques and neurofibrillary tangles. Antemortem diagnosis is based on the presence and progressive worsening of clinical symptoms. Clinical diagnosis is challenging, because other causes of dementia are often difficult to differentiate from AD. Accordingly, researchers are actively evaluating a variety of clinical-, imaging-, and laboratory-based methods to distinguish AD and non-AD dementia through antemortem detection of AD pathology. These methods include MRI to quantify brain atrophy, fluorodeoxyglucose–positron emission tomography to characterize loss of metabolic function, positron emission tomography and single photon emission computed tomography to define amyloid plaque burden, measurement of cerebrospinal fluid (CSF) concentrations of total tau (t-tau) and tau phosphorylated at threonine181 (P-tau181) to detect neuronal degeneration, and measurement of a 42 amino acid isoform of amyloid β (Aβ1–42) in CSF to detect abnormal trafficking of this peptide present in amyloid plaque. Several studies, including the Alzheimer’s Disease Neuroimaging Initiative (ADNI), have provided compelling evidence that CSF t-tau, P-tau181, and Aβ1–42 measurements can identify individuals with clinically and pathologically diagnosed AD. Moreover, these studies suggest that these 3 CSF biomarkers can identify asymptomatic individuals and patients with mild cognitive impairment (MCI) likely to progress to AD (2). In a new …