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
10 Reads
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "[34] x 39 187 – – Concentration of CSF tau, p-tau 181 , and Ab 42 were associated with future development of AD from MCI. [37] 259 415 146 – Provides evidence for detection of different aspects of AD Ab pathology by CSF Ab 1–42 compared with amyloid PET (Florbetapir) [39] x 90 – 49 – CSF Ab 42 level corresponded with the findings of brain amyloid imaging (PiB-PET), and CSF t-tau/Ab 42 ratio predicted future dementia in cognitively normal elderly. [40] x 304 750 529 – Combination of CSF Ab 42 /p-tau and CSF t-tau identified incipient AD. [41] x – 137 – – CSF Ab 42 levels are fully decreased at least 5–10 years before conversion to AD. CSF t-tau and p-tau increased later than Ab 42 . [42] x 251 236 631 267 T-tau/Ab 42 ratio of .0.52 constitutes a robust CSF AD profile, and was validated in the validation cohort (N 5 1442). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1-42), t-tau, and p-tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1-42, t-tau, and p-tau181 data. CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials. Copyright © 2015. Published by Elsevier Inc.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2015; 11(7):772-91. DOI:10.1016/j.jalz.2015.05.003 · 12.41 Impact Factor
  • Source
    • ". This might be attributable to the heterogeneity of the study population as well as the discrepant continuum between the pathophysiological process of AD and its clinical symptomatology, as studies have shown that altered A␤ metabolism precedes tau-related pathology, neuronal degeneration, and clinical symptoms [44] [45]. It is also unclear if the APOE genotype influences the CSF biomarkers-based risk classification of AD in some studies [4] [46]; however we found no significant difference of APOE ␧4 carrier status by quintile/risk level groups and no significant interaction between APOE ␧4 carrier status and quintiles of multi-biomarker scores using Cox PH model. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Background: Cerebrospinal fluid (CSF) biomarkers can distinguish Alzheimer’s disease (AD) patients from normal controls; however, their interpretation and potential for use in patients with mild cognitive impairment (MCI) remains unclear. Objective: To examine whether biomarker levels allow for risk stratification among MCI patients who are at increased risk to develop AD, thus allowing for improved targeting of early interventions for those whose risk are higher. Methods: We analyzed data from the Alzheimer’s Disease Neuroimaging Initiative on MCI patients (n = 195) to estimate their risk of developing AD for up to 6 years on the basis of baseline CSF biomarkers. We used time-dependent receiver operating characteristic analysis to identify the best combination of biomarkers to discriminate those who converted to AD from those who remained stable. We used these data to construct a multi-biomarker score and estimated the risk of progression to AD for each quintile of the multi-biomarker score. Results: We found that Aβ 1-42 and P-tau181p were the best combination among CSF biomarkers to predict the overall risk of developing AD among MCI patients (area under the curve = 0.77). The hazard ratio of developing AD among MCI patients with high-risk (3rd–5th quintiles) biomarker levels was about 4 times greater than MCI patients with low-risk (1st quintile) levels (95% confidence interval, 1.93–7.26). Conclusion: Our study identifies MCI patients at increased risk of developing AD by applying a multi-biomarker score using CSF biomarker results. Our findings may be of value to MCI patients and their clinicians for planning purposes and early intervention as well as for future clinical trials.
    Journal of Alzheimer's disease: JAD 01/2015; 47(3):729-740. DOI:10.3233/JAD-150066 · 4.15 Impact Factor
Show more