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

Neuropsychiatric Clinic, Skåne University Hospital, Malmö, Sweden.
Archives of general psychiatry (Impact Factor: 13.75). 01/2012; 69(1):98-106. DOI: 10.1001/archgenpsychiatry.2011.155
Source: PubMed

ABSTRACT 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.
To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-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.
A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).
Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. MAIN OUTCOME MEASURE Conversion to AD dementia.
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%.
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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: CSF biomarkers’ performance for predicting conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) is still suboptimal. Objective: By considering several confounding factors we aimed to identify in which situations these CSF biomarkers can be useful. Data sources: A systematic review was conducted on MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane, and CRD (1990-2013). Eligibility criteria: 1) prospective studies of CSF biomarkers’ performance for predicting conversion from MCI to AD/dementia; 2) inclusion of Aß42 and T-tau and/or p-tau. Several meta-analyses were performed. Results: Aß42/p-tau ratio had high capacity to predict conversion to AD in MCI patients younger than 70 years. P-tau had high capacity to identify MCI cases converting to AD in ≤24 months. Conclusions: Explaining how different confounding factors influence CSF biomarkers’ predictive performance is mandatory to elaborate a definitive map of situations where these CSF biomarkers are useful both in clinics and research.
    Frontiers in Aging Neuroscience 09/2014; 6:287. DOI:10.3389/fnagi.2014.00287 · 2.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The goal of the present study was to determine the earliest patterns of hypometabolism and atrophy in the development of Alzheimer's disease (AD). Stages of AD were defined by positron emission tomography imaging evidence of cortical amyloid pathology in addition to cognitive criteria. Subjects for the study were selected from the Alzheimer's Disease Neuroimaging Initiative database and divided into 4 groups: cognitively normal (CN) amyloid negative (Aβ-) elderly subjects (n = 36), CN amyloid-positive (Aβ+) (n = 21), early mild cognitive impairment Aβ+ (n = 65), and late mild cognitive impairment Aβ+ (n = 23) subjects. Region of interest-based (primary) and voxel-based (secondary) analyses were used to assess gray matter hypometabolism, quantified by [18F]fluorodeoxyglucose-positron emission tomography, and decrease in gray matter volume and cortical thickness was measured by magnetic resonance imaging. Region of interest- and voxel-based analyses showed significant hypometabolism but not atrophy in CN Aβ+ subjects compared with CN Aβ- subjects. The results suggest that hypometabolism exceeds atrophy in preclinical AD, supporting the notion that amyloid load may affect synaptic activity, leading to synaptic loss and subsequent neuronal loss.
    Neurobiology of aging 04/2014; DOI:10.1016/j.neurobiolaging.2014.04.006 · 4.85 Impact Factor
  • Source