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.

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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. "
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    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.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 11/2015; DOI:10.1016/j.jalz.2015.09.009 · 12.41 Impact Factor
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    • "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. "
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    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.
    Journal of Alzheimer's disease: JAD 09/2015; 48(s1). DOI:10.3233/JAD-150202 · 4.15 Impact Factor
    • "In the AD neuroimaging initiative (ADNI) study, an AD CSF biomarker profile was present in >80% of AD patients, including those with amnestic MCI who progressed to AD [7] [8]. Previous research into the determination of the optimal AD CSF biomarker metrics has also shown the utility of composite measurements, especially those employing the T-tau or P-tau 181P to A 1-42 ratios [8] [11] [16] [23] [24]. Similar to these studies, we observed that in general, the ratios offered the best sensitivity and specificity (92–96% and 88–93% respectively), suggesting these may be the optimal AD CSF diagnostic biomarker metrics. "
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    ABSTRACT: Background: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). Objective: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Methods: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. Results: CSF Aβ1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ1-42 to predict MCI/AD, reached ≥92% sensitivity and specificity. Conclusions: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.
    Journal of Alzheimer's disease: JAD 09/2015; 48(1):175-187. DOI:10.3233/JAD-150247 · 4.15 Impact Factor
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