Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease

Palmqvist, Sebastian; Zetterberg, Henrik; Mattsson, Niklas; Johansson, Per; Minthon, Lennart; Blennow, Kaj; Olsson, Mattias; Hansson, Oskar

doi:10.1212/wnl.0000000000001991

Cited by 307 publications

(228 citation statements)

References 40 publications

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“…In that study, increased amyloid deposition by PET, but not CSF Aβ42, significantly correlated with disease stage among patients with mild cognitive symptoms. The same authors recently reported that the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage AD is comparable [34]. A previously published report, with similar design to the present study, failed to demonstrate an association between CSF biomarkers and cognitive decline in non-demented elderly [31].…”

Section: Discussionsupporting

confidence: 64%

Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults

Dumurgier

Hanseeuw

Hatling

et al. 2017

JAD

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Background Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer’s disease (AD) modifying therapies move towards preclinical stages. Objective To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults. Methods 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer’s Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of beta-amyloid 1-42 (Ab42), total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) in the CSF at study entry were available in all cases. Baseline brain MRI, FDG-PET and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models. Results 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score. Conclusions Baseline CSF t-Tau and p-Tau181, in vivo amyloid load and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest.

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Section: Discussionsupporting

confidence: 64%

Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults

Dumurgier

Hanseeuw

Hatling

et al. 2017

JAD

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“…In early-onset FAD, Aβ42 levels were reduced already 25 years before cognitive symptoms [403]. The inverse correlation between Aβ42 in the cerebrospinal fluid and extracellular insoluble plaque deposits from PET imaging [404] strongly indicates that the soluble pools of Aβ42 have been depleted in favor of the deposits; since the deposits are not pathogenic, depletion of soluble Aβ42 seems consistent with loss of soluble Aβ from the neurons, i.e. if the overall soluble pool of functional Aβ has been depleted in favor of non.functional oligomers and aggregates.…”

Section: Loss Of Function Is Consistent With Aβ-related Biomarkers Ofmentioning

confidence: 94%

Alzheimer’s disease due to loss of function: A new synthesis of the available data

Kepp

2016

Progress in Neurobiology

120

107

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Alzheimer's Disease (AD) is a highly complex disease involving a broad range of clinical, cellular, and biochemical manifestations that are currently not understood in combination. This has led to many views of AD, e.g. the amyloid, tau, presenilin, oxidative stress, and metal hypotheses. The amyloid hypothesis has dominated the field with its assumption that buildup of pathogenic β-amyloid (Aβ) peptide causes disease. This paradigm has been criticized, yet most data suggest that Aβ plays a key role in the disease. Here, a new loss-of-function hypothesis is synthesized that accounts for the anomalies of the amyloid hypothesis, e.g. the curious pathogenicity of the Aβ42/Aβ40 ratio, the loss of Aβ caused by presenilin mutation, the mixed phenotypes of APP mutations, the poor clinical-biochemical correlations for genetic variant carriers, and the failure of Aβ reducing drugs. The amyloid-loss view accounts for recent findings on the structure and chemical features of Aβ variants and their coupling to human patient data. The lost normal function of APP/Aβ is argued to be metal transport across neuronal membranes, a view with no apparent anomalies and substantially more explanatory power than the gain-of-function amyloid hypothesis. In the loss-of-function scenario, the central event of Aβ aggregation is interpreted as a loss of soluble, functional monomer Aβ rather than toxic overload of oligomers. Accordingly, new research models and treatment strategies should focus on remediation of the functional amyloid balance, rather than strict containment of Aβ, which, for reasons rationalized in this review, has failed clinically.

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“…CSF levels of Aβ42 and Aβ40 were analyzed with Euroimmun immunoassay (EUROIMMUN AG, Lübeck, Germany)2324 in all study participants. This was done before the analysis of plasma samples using Simoa platform.…”

Section: Methodsmentioning

confidence: 99%

Plasma β-amyloid in Alzheimer’s disease and vascular disease

Bateman

Stomrud

Palmqvist

et al. 2016

Sci Rep

Self Cite

494

436

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Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aβ42 and Aβ40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aβ42 and Aβ40, and negative correlations between plasma Aβ42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aβ42 and Aβ40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aβ42 was just moderately decreased whereas Aβ40 levels were unchanged. Higher plasma (but not CSF) levels of Aβ were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aβ is overtly decreased during the dementia stage of AD indicating that prominent changes in Aβ metabolism occur later in the periphery compared to the brain. Further, increased levels of Aβ in plasma are associated with vascular disease.

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Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease

Cited by 307 publications

References 40 publications

Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults

Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults

Alzheimer’s disease due to loss of function: A new synthesis of the available data

Plasma β-amyloid in Alzheimer’s disease and vascular disease

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