Amyloid Biomarkers in Alzheimer’s

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  • Amyloid biomarkers




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    TIPS-1217; No. of Pages 13olism or pathology to guide dosage. Two types of amy-loid biomarker have been developed: Ab-binding ligandsfor use in positron emission tomography (PET) andassays to measure Ab42 in cerebrospinal fluid (CSF).In this review, we present the rationales behind thesebiomarkers and compare their ability to measure Abplaque load in the brain. We also review possible short-comings and the need of standardization of both bio-markers, as well as their implementation in the clinic.

    Amyloid in Alzheimers diseaseAmyloid is the term used for proteins that are misfoldedinto a cross b-sheet structure and thereby bind dyes suchas Congo Red and Thioflavin T [1]. AD is one of the majoramyloidoses, with two types of amyloid deposited in thebrain: (i) Ab forming aggregates in the form of plaques andcerebrovascular amyloid angiopathy (CAA); and (ii) tauprotein, which forms neurofibrillary tangles, dystrophicneurites, and neuropil threads (reviewed in [2]). When

    leading to cognitive impairment and finally dementia[3]. AD research advances have also generated a largenumber of drug candidates with potential disease-modify-ing effects. Based on the strong belief in the amyloidcascade hypothesis, researchers have placed an over-whelming focus on molecules targeting Ab productionand aggregation in AD drug development, and most drugcandidates tested aim to inhibit Ab toxicity by reducingfurther Ab aggregation and plaque formation. These drugcandidates include secretase inhibitors to lower Ab pro-duction from APP, Ab aggregation inhibitors to inhibit Aboligomerization or fibrillization, as well as active andpassive Ab immunotherapies designed to capture eithersoluble or aggregated Ab, or both, which will be eitherdegraded or cleared from the brain (reviewed in [4]).

    Alarmingly, an increasing number of large Phase IIIclinical trials on Ab targeting drugs have reported nobeneficial effects on cognitive symptoms in patients withsporadic AD [57]. These discouraging reports have causedincreasing concern in the AD research community that theamyloid cascade hypothesis eventually will be falsified,that is, that Ab aggregation is just a bystander, and notthe cause, of neurodegeneration in AD [8]. A more optimis-tic viewpoint is that there are several logical explanationsfor the trial failures, including that the trials enrolled


    2015 Elsevier Ltd. All rights reserved.

    Corresponding author: Blennow, K. ([email protected]).Keywords: Alzheimers disease; biomarker; b-amyloid (Ab); cerebrospinal fluid;positron emission tomography (PET).diseaseKaj Blennow1,2, Niklas Mattsson1,3,4, MicHenrik Zetterberg1,9

    1Clinical Neurochemistry Laboratory, Institute of NeuroscienceGothenburg, Molndal, Sweden2The Torsten Soderberg Professorship at the Royal Swedish A3Department of Veterans Affairs Medical Center, Center for Ima4Department of Radiology and Biomedical Imaging, University5Helen Wills Neuroscience Institute, University of California, Be6Department of Clinical Neuroscience and Rehabilitation, Unive7Department of Clinical Sciences, Lund University, Lund, Swed8Clinical Memory Research unit, Clinical Sciences, Lund Univer9UCL Institute of Neurology, Queen Square, London, UK

    Aggregation of amyloid-b (Ab) into oligomers, fibrils,and plaques is central in the molecular pathogenesis ofAlzheimers disease (AD), and is the main focus of ADdrug development. Biomarkers to monitor Ab metabo-lism and aggregation directly in patients are importantfor further detailed study of the involvement of Ab indisease pathogenesis and to monitor the biochemicaleffect of drugs targeting Ab in clinical trials. Further-more, if anti-Ab disease-modifying drugs prove to beeffective clinically, amyloid biomarkers will be of specialvalue in the clinic to identify patients with brain amyloiddeposition at risk for progression to AD dementia, toenable initiation of treatment before neurodegenerationis too severe, and to monitor drug effects on Ab metab- in Alzheimers

    el Scho ll5,6, Oskar Hansson7,8, and

    d Physiology, The Sahlgrenska Academy at University of

    emy of Sciencesg of Neurodegenerative Diseases, San Francisco, CA, USACalifornia, San Francisco, CA, USAley, CA, USAty of Gothenburg, Gothenburg, Sweden

    , Lund, Sweden

    not specified otherwise, we use the term amyloid hereto refer to Ab pathology rather than tau pathology.

    Research advances during the past two decades haveresulted in detailed knowledge on disease mechanisms. Abis produced by the sequential cleavage of amyloid precur-sor protein (APP) by two enzymes, b-site APP-cleavingenzyme 1 (BACE1), also called b-secretase, and the g-secretase complex (Figure 1). The prevailing hypothesisfor AD pathogenesis is called the amyloid cascade hypoth-esis (Figure 2), posing that Ab aggregation is the initiatingmechanistic event, in which the different stages of aggre-gates, from soluble oligomers to insoluble fibrils in plaques,are believed to impair synaptic function and ultimatelydamage neurons, resulting in chronic neurodegenerationTrends in Pharmacological Sciences xx (2015) 113 1

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    TIPS-1217; No. of Pages 13patients with AD and dementia, which is probably tooadvanced a stage of the disease to enable this type of drugto show any effect on clinical symptoms, and that trialpatients have been diagnosed based on purely clinicalcriteria, which are too nonspecific; thus, trials will com-prise a cohort with only approximately 80% of enrolledpatients having genuine AD pathology [9]. Both of theseshortcomings call for diagnostic biomarkers to aid clini-cians in making an early and accurate diagnosis. In futureclinical trials on Ab-targeting drugs, amyloid biomarkerswould be especially valuable to confirm that enrolledpatients do have Ab pathology and, thus, the disease forwhich the drug is intended, which would increase thepossibility of identifying a positive clinical effect of the



    Full-length APP

    Figure 1. Generation of b-amyloid (Ab) by metabolism of amyloid precursor protei

    domain is partly embedded in the plasma membrane, with 28 amino acids outside t

    APP-cleaving enzyme 1 (BACE1), also called b-secretase, and a large soluble part

    cleaved by g-secretase, releasing soluble Ab. g-secretase is an intramembranous p

    nicastrin, presenilin enhancer (Pen-2), and anterior pharynx-defective (Aph-1).

    Reviewdrug [10]. If drug effects will be seen only in subjects withbiomarker evidence of pathology, such biomarkers wouldalso be useful to guide clinical decisions on whether toprescribe Ab-targeting drugs, once these are available.

    Another possible explanation for some of the trial fail-ures is that poor drug candidates have been taken to PhaseII and III clinical trials based on promising, but mislead-ing data from preclinical drug development [2]. It has beencommon in AD drug development to test whether novel Abdrug candidates reduce the Ab plaque load in AD trans-genic mice and, if so, take the drug into large and expen-sive clinical trials without examining whether targetengagement can be verified in humans. There are numer-ous examples of failed trials (e.g., tarenflurbil and phen-serine), which probably are due to the poor predictivepower of these disease models [2,9]. For this reason, itis becoming increasingly common to apply theragnosticbiomarkers during the early stages of AD drug develop-ment [5,1113]. In this context, amyloid biomarkersapplied in short small-scale trials to prove target engage-ment in Phase I proof-of-principle studies on healthyvolunteers [9] or Phase II proof-of-concept studies inpatients with AD [11] may be valuable in the selectionof drug candidates and may improve success rates in late-stage clinical trials.

    2In contrast to most other neurodegenerative brain dis-orders, a set of biomarkers has been developed for thedifferent pathogenic processes in AD and examined in alarge number of clinical studies. These AD biomarkersinclude magnetic resonance imaging (MRI) of hippocampalor whole-brain atrophy, PET evaluation of glucose metab-olism in cortical neurons and glial cells, CSF assays tomeasure tau protein, reflecting the intensity of the neuro-nal degeneration, and phosphorylated tau, reflecting thepresence of tangles, and the two amyloid biomarkersamyloid PET and CSF Ab42 (reviewed in [14]). In thisreview, we focus on the amyloid biomarkers, which havebeen much examined and reviewed individually, while anobjective head-to-head comparison on their performance to

    -CTF (C99)





    TRENDS in Pharmacological Sciences

    PP). APP is a transmembrane protein with a large extracellular N terminus. The Ab

    embrane and 14 amino acids embedded in the membrane. APP is cleaved by b-site

    Pb) is released. The remaining C-terminal fragment, called b-CTF or C99, is then

    ase complex, with four components, the active enzyme presenilin, together with

    Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. xmeasure Ab plaque load or Ab metabolism in the brainis lacking. We also discuss mechanistic differences betweenthe amyloid biomarkers and their implementation inclinical trials and in the clinical routine management ofpatients with cognitive symptoms.

    Biomarkers for ADAccording to the National Institutes of Health (NIH) Bio-markers Definitions Working Group, a biomarker is de-fined as a characteristic that is objectively measured andevaluated as an indicator of normal biological processes,pathogenic processes, or pharmacologic responses to atherapeutic intervention [15]. While the National CancerInstitute at the NIH defines a bioma