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: 14.48). 01/2012; 69(1):98-106. DOI: 10.1001/archgenpsychiatry.2011.155
Source: PubMed


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.

Download full-text


Available from: Oskar Hansson, Sep 22, 2015
    • "Candidate biomarkers include decreased amyloid-beta 1–42 (Ab [1–42]) in the cerebrospinal fluid (CSF), alone or in conjunction with increased total tau or phosphorylated tau, and increased retention of amyloidtargeting radiotracers detected by positron emission tomography (PET). CSF Ab (1–42) is altered early in the course of the illness [5] [6], and CSF Ab (1–42) levels correlate well with neuropathologic findings (neuritic plaques) consistent with AD [7] [8], as well as with PET-based measurements of amyloid pathology [9] [10] [11]. These findings support the use of CSF Ab (1–42) in research diagnostic criteria. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Available assays for quantitation of the Alzheimer's disease (AD) biomarker amyloid-beta 1-42 (Aβ [1-42]) in cerebrospinal fluid demonstrate significant variability and lack of standardization to reference measurement procedures (RMPs). We report analytical performance data for the novel Elecsys β-amyloid (1-42) assay (Roche Diagnostics). Methods: Lot-to-lot comparability was tested using method comparison. Performance parameters were measured according to CLSI guidelines. The assay was standardized to a candidate RMP. Results: Limit of quantitation was <11.28 pg/mL, and the assay was linear throughout the measuring range (200-1700 pg/mL). Excellent lot-to-lot comparability was observed (correlation coefficients [Pearson's r] >0.995; bias in medical decision area <2%). Repeatability coefficients of variation (CVs) were 1.0%-1.6%, intermediate CVs were 1.9%-4.0%, and intermodule CVs were 1.1%-3.9%. Estimated total reproducibility was 2.0%-5.1%. Correlation with the RMP was good (Pearson's r, 0.93). Discussion: The Elecsys β-amyloid (1-42) assay has high analytical performance that may improve biomarker-based AD diagnosis.
    No preview · Article · Nov 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
    • "The latter finding confirms that a specific association exists between injury markers (i.e., ttau ) and executive function; this association is not surprising because executive processes are involved in various higher-level operations and may therefore reflect global cognitive status. Finally, both findings are concordant with the temporal course of AD, which includes an earlier onset of amyloid pathology versus tau-mediated injury (Buchhave et al., 2012;Jack et al., 2011Jack et al., , 2013). Indeed, there is evidence that decreased Aβ 42 levels are associated with cognitive dysfunction in early disease stages, whereas t-tau levels are more indicative of performance during later disease stages (Rolstad et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Memory and executive deficits are important cognitive markers of Alzheimer's disease (AD). Moreover, in the past decade, cerebrospinal fluid (CSF) biomarkers have been increasingly utilized in clinical practice. Both cognitive and CSF markers can be used to differentiate between AD patients and healthy seniors with high diagnostic accuracy. However, the extent to which performance on specific mnemonic or executive tasks enables reliable estimations of the concentrations of different CSF markers and their ratios remains unclear.
    No preview · Article · Nov 2015 · Experimental gerontology
  • Source
    • "Similar results have been obtained in two other studies, in which CSF A 1-42 exhibits the strongest association with cognitive performance in cognitively normal individuals or individuals with SCD, whereas CSF T-tau predominantly shows such associations in MCI and dementia stages of AD [45] [46]. The longest follow-up study so far extends over 10 years in a population of MCI subjects [47]. Approximately 90% of the MCI subjects with pathologic CSF biomarker levels at baseline have developed AD within 10 years. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is evolving evidence that individuals categorized with subjective cognitive decline (SCD) are potentially at higher risk for developing objective and progressive cognitive impairment compared to cognitively healthy individuals without apparent subjective complaints. Interestingly, SCD, during advancing preclinical Alzheimer's disease (AD), may denote very early, subtle cognitive decline that cannot be identified using established standardized tests of cognitive performance. The substantial heterogeneity of existing SCD-related research data has led the Subjective Cognitive Decline Initiative (SCD-I) to accomplish an international consensus on the definition of a conceptual research framework on SCD in preclinical AD. In the area of biological markers, the cerebrospinal fluid signature of AD has been reported to be more prevalent in subjects with SCD compared to healthy controls; moreover, there is a pronounced atrophy, as demonstrated by magnetic resonance imaging, and an increased hypometabolism, as revealed by positron emission tomography, in characteristic brain regions affected by AD. In addition, SCD individuals carrying an apolipoprotein ɛ4 allele are more likely to display AD-phenotypic alterations. The urgent requirement to detect and diagnose AD as early as possible has led to the critical examination of the diagnostic power of biological markers, neurophysiology, and neuroimaging methods for AD-related risk and clinical progression in individuals defined with SCD. Observational studies on the predictive value of SCD for developing AD may potentially be of practical value, and an evidence-based, validated, qualified, and fully operationalized concept may inform clinical diagnostic practice and guide earlier designs in future therapy trials.
    Full-text · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.