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      Current state of Alzheimer’s fluid biomarkers

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          Abstract

          Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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          Neuroinflammation in Alzheimer's disease: Current evidence and future directions.

          Several attempts have been made to treat Alzheimer's disease (AD) using anti-amyloid strategies with disappointing results. It is clear that the "amyloid cascade hypothesis" alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies. Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful. In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression. We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro-inflammatory factors, and neuronal damage. We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target.
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            Sex differences in Alzheimer disease — the gateway to precision medicine

            Alzheimer disease (AD) is characterized by wide heterogeneity in cognitive and behavioural syndromes, risk factors and pathophysiological mechanisms. Addressing this phenotypic variation will be crucial for the development of precise and effective therapeutics in AD. Sex-related differences in neural anatomy and function are starting to emerge, and sex might constitute an important factor for AD patient stratification and personalized treatment. Although the effects of sex on AD epidemiology are currently the subject of intense investigation, the notion of sex-specific clinicopathological AD phenotypes is largely unexplored. In this Review, we critically discuss the evidence for sex-related differences in AD symptomatology, progression, biomarkers, risk factor profiles and treatment. The cumulative evidence reviewed indicates sex-specific patterns of disease manifestation as well as sex differences in the rates of cognitive decline and brain atrophy, suggesting that sex is a crucial variable in disease heterogeneity. We discuss critical challenges and knowledge gaps in our current understanding. Elucidating sex differences in disease phenotypes will be instrumental in the development of a 'precision medicine' approach in AD, encompassing individual, multimodal, biomarker-driven and sex-sensitive strategies for prevention, detection, drug development and treatment.
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              Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

              To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.
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                Author and article information

                Contributors
                +46 31 3431791 , kaj.blennow@neuro.gu.se
                Journal
                Acta Neuropathol
                Acta Neuropathol
                Acta Neuropathologica
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0001-6322
                1432-0533
                28 November 2018
                28 November 2018
                2018
                : 136
                : 6
                : 821-853
                Affiliations
                [1 ]ISNI 0000 0001 2172 2676, GRID grid.5612.0, BarcelonaBeta Brain Research Center, Fundació Pasqual Maragall, , Universitat Pompeu Fabra, ; Barcelona, Spain
                [2 ]ISNI 0000 0000 9635 9413, GRID grid.410458.c, Unidad de Alzheimer y otros trastornos cognitivos, , Hospital Clinic-IDIBAPS, ; Barcelona, Spain
                [3 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, , University of Melbourne, ; Parkville, VIC Australia
                [4 ]Roche Centralised and Point of Care Solutions, Roche Diagnostics International, Rotkreuz, Switzerland
                [5 ]Neuroscience Therapeutic Area Unit, Takeda Development Centre Americas Ltd, Cambridge, MA USA
                [6 ]ISNI 0000 0004 0374 1269, GRID grid.417570.0, Genentech, A Member of the Roche Group, ; Basel, Switzerland
                [7 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Cleveland Clinic Lou Ruvo Center for Brain Health, ; Las Vegas, NV USA
                [8 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Neurology, , Washington University in St. Louis, ; St. Louis, MO USA
                [9 ]GRID grid.453198.2, AXA Research Fund and Sorbonne University Chair, ; Paris, France
                [10 ]ISNI 0000 0001 2150 9058, GRID grid.411439.a, Sorbonne University, GRC No 21, , Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, ; Paris, France
                [11 ]ISNI 0000 0001 2150 9058, GRID grid.411439.a, Brain and Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, ; Paris, France
                [12 ]ISNI 0000 0001 2150 9058, GRID grid.411439.a, Department of Neurology, Institute of Memory and Alzheimer’s Disease (IM2A), , Pitié-Salpêtrière Hospital, AP-HP, ; Paris, France
                [13 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Departments of Epidemiology and Neurology, , Mayo Clinic, ; Rochester, MN USA
                [14 ]ISNI 0000 0004 0384 8146, GRID grid.417832.b, Biomarkers, Biogen, ; Cambridge, MA USA
                [15 ]ISNI 0000 0000 9765 6057, GRID grid.266871.c, Department of Pharmacology and Neuroscience; Institute for Healthy Aging, , University of North Texas Health Science Center, ; Fort Worth, TX USA
                [16 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Neurology and Alzheimer Center, , VU University Medical Center, ; Amsterdam, The Netherlands
                [17 ]ISNI 0000 0004 0374 1269, GRID grid.417570.0, Roche Innovation Center Basel, , F. Hoffmann-La Roche, ; Basel, Switzerland
                [18 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Pathology and Laboratory Medicine, and Center for Neurodegenerative Disease Research, , University of Pennsylvania, ; Philadelphia, PA USA
                [19 ]ISNI 0000 0004 0572 4227, GRID grid.431072.3, Clinical Development Neurology, AbbVie, ; North Chicago, IL USA
                [20 ]GRID grid.419796.4, Lundbeck, ; Deerfield, IL USA
                [21 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, , Perelman School of Medicine at the University of Pennsylvania, ; Philadelphia, PA USA
                [22 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, Department of Psychiatry and Neurochemistry, , The Sahlgrenska Academy at the University of Gothenburg, ; Mölndal, Sweden
                [23 ]ISNI 000000009445082X, GRID grid.1649.a, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal Campus, , Sahlgrenska University Hospital, ; 431 80 Mölndal, Sweden
                [24 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Molecular Neuroscience, , UCL Institute of Neurology, ; Queen Square, London, UK
                [25 ]UK Dementia Research Institute at UCL, London, UK
                Article
                1932
                10.1007/s00401-018-1932-x
                6280827
                30488277
                c73ef249-4c2e-4fe3-a927-fd3ea1f19019
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 17 September 2018
                : 5 November 2018
                : 7 November 2018
                Funding
                Funded by: Roche Diagnostics International
                Categories
                Review
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Neurology
                alzheimer’s disease,amyloid,biomarker,blood,cerebrospinal fluid,tau
                Neurology
                alzheimer’s disease, amyloid, biomarker, blood, cerebrospinal fluid, tau

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