CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis

Olsson, Bob; Lautner, Ronald; Andréasson, Ulf; Öhrfelt, Annika; Portelius, Erik; Bjerke, Maria; Hölttä, Mikko; Rosén, Christoffer; Olsson, Caroline; Strobel, Gabrielle; Wu, Elizabeth; Dakin, Kelly; Petzold, Max; Blennow, Kaj; Zetterberg, Henrik

doi:10.1016/s1474-4422(16)00070-3

Cited by 1,507 publications

(1,461 citation statements)

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“…Prior major cohort studies have reported that plasma A β is a risk factor or predictive marker for AD onset in healthy older community members aged at least 55 years 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. In contrast, after analyzing fasting blood samples from healthy individuals of a wide age range, we observed the natural course of and factors affecting plasma A β 40 and A β 42.…”

Section: Discussionmentioning

confidence: 99%

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Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

Nakamura

Kawarabayashi

Seino

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe aim of this study was to confirm determinative factors for plasma Aβ and its association with cognitive function.MethodsFasting plasma Aβ40 and Aβ42 levels were measured by ELISA in 1019 participants in the Iwaki Health Promotion Project. The relationships between plasma Aβ and health‐related items, including physical characteristics, cognitive function tests, blood chemistry, and APOE‐ε4 genotype were analyzed.ResultsThe plasma levels of Aβ40 and Aβ42, and Aβ40/42 ratio were found to significantly increase with aging. The age‐dependent increase in Aβ42 level was significantly suppressed by APOE‐ε4. Renal function was an associated factor for the plasma Aβ40 level. The plasma Aβ42 level and Aβ40/42 ratio correlated with cognitive function.InterpretationAge and APOE‐ε4 are major determinative factors of plasma levels of Aβ42 and the Aβ40/42 ratio. These factors are critical adjustment factors for the usage of plasma Aβ as a biomarker of central nervous system amyloidosis.

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Section: Discussionmentioning

confidence: 99%

“…Systematic reviews and meta‐analyses have also suggested that the plasma A β 40/42 ratio can predict the development of AD and dementia 7. However, these findings indicated significant heterogeneity,7 and plasma levels of A β 40 and A β 42 alone were not significantly associated 8, 9…”

Section: Introductionmentioning

confidence: 99%

Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

Nakamura

Kawarabayashi

Seino

et al. 2018

Ann Clin Transl Neurol

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“…A β 42, total‐tau (t‐tau), and phosphorylated tau (p‐tau) are now considered the major CSF biomarkers in AD pathogenesis, and they have been included as research criteria for the diagnosis of AD since 2007 10. Apart from these core CSF biomarkers, neurofilament light protein (NFL) and plasma t‐tau have also been reported to be associated with AD 11. CSF surrounds the brain, acting as a protective cushion for the brain and spine, and is in direct contact with the interstitial fluid of the brain.…”

Section: Introductionmentioning

confidence: 99%

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Sengupta

Portelius

Hansson

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWith an increasing incidence of Alzheimer's disease (AD) and neurodegenerative tauopathies, there is an urgent need to develop reliable biomarkers for the diagnosis and monitoring of the disease, such as the recently discovered toxic tau oligomers. Here, we aimed to demonstrate the presence of tau oligomers in the cerebrospinal fluid (CSF) of patients with cognitive deficits, and to determine whether tau oligomers could serve as a potential biomarker for AD.MethodsA multicentric collaborative study involving a double‐blinded analysis with a total of 98 subjects with moderate to severe AD (N = 41), mild AD (N = 31), and nondemented control subjects (N = 26), and two pilot studies of 33 total patients with AD (N = 19) and control (N = 14) subjects were performed. We carried out biochemical assays to measure oligomeric tau from CSF of these patients with various degrees of cognitive impairment as well as cognitively normal controls.ResultsUsing a highly reproducible indirect ELISA method, we found elevated levels of tau oligomers in AD patients compared to age‐matched controls. Western blot analysis confirmed the presence of oligomeric forms of tau in CSF. In addition, the ratio of oligomeric to total tau increased in the order: moderate to severe AD, mild AD, and controls.ConclusionThese assays are suitable for the analysis of human CSF samples. These results here suggest that CSF tau oligomer measurements could be optimized and added to the panel of CSF biomarkers for the accurate and early detection of AD.

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“…A recent meta-analysis reported plasma tau as the only blood-based biomarker to delineate AD from controls [4]. Fortunately, a new ultrasensitive technique was developed capable of detecting tau at low concentrations in plasma [5].…”

Section: Introductionmentioning

confidence: 99%

Plasma Tau Association with Brain Atrophy in Mild Cognitive Impairment and Alzheimer’s Disease

Deters

Risacher

Kim

et al. 2017

JAD

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Abstract.Background: Peripheral (plasma) and central (cerebrospinal fluid, CSF) measures of tau are higher in Alzheimer's disease (AD) relative to prodromal stages and controls. While elevated CSF tau concentrations have been shown to be associated with lower grey matter density (GMD) in AD-specific regions, this correlation has yet to be examined for plasma in a large study. Objective: Determine the neuroanatomical correlates of plasma tau using voxel-based analysis. Methods: Cross-sectional data for 508 ADNI participants were collected for clinical, plasma total-tau (t-tau), CSF amyloid (A␤ 42 ) and tau, and MRI variables. The relationship between plasma tau and GMD and between CSF t-tau and GMD were assessed on a voxel-by-voxel basis using regression models. Age, sex, APOE ε4 status, diagnosis, and total intracranial volume were used as covariates where appropriate. Participants were defined as amyloid positive (A␤+) if CSF A␤ 42 was <192 pg/mL. Results: Plasma tau was negatively correlated with GMD in the medial temporal lobe (MTL), precuneus, thalamus, and striatum. The associations with thalamus and striatum were independent of diagnosis. A negative correlation also existed 1 Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/ wp-content/uploads/how to apply/ADNI Acknowledgement List. pdf. K.D. Deters et al. / Plasma Tau is Associated with Brain Atrophybetween plasma tau and GMD in A␤+ participants in the MTL, precuneus, and frontal lobe. When compared to CSF t-tau, plasma tau showed a notably different associated brain atrophy pattern, with only small overlapping regions in the fusiform gyrus. Conclusion: Plasma tau may serve as a non-specific marker for neurodegeneration but is still relevant to AD considering low GMD was associated with plasma tau in A␤+ participants and not A␤-participants.

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CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis

Abstract: Swedish Research Council, Swedish State Support for Clinical Research, Alzheimer's Association, Knut and Alice Wallenberg Foundation, Torsten Söderberg Foundation, Alzheimer Foundation (Sweden), European Research Council, and Biomedical Research Forum.

Cited by 1,507 publications

References 32 publications

Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Plasma Tau Association with Brain Atrophy in Mild Cognitive Impairment and Alzheimer’s Disease

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