5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?

      review-article
      1 , 2 , 3 , * , , 4 , * ,
      PLoS Biology
      Public Library of Science

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Strong genetic evidence supports an imbalance between production and clearance of amyloid β-protein (Aβ) in people with Alzheimer disease (AD). Microglia that are potentially involved in alternative mechanisms are actually integral to the amyloid cascade. Fluid biomarkers and brain imaging place accumulation of Aβ at the beginning of molecular and clinical changes in the disease. So why have clinical trials of anti-amyloid therapies not provided clear-cut benefits to patients with AD? Can anti-amyloid therapies robustly decrease Aβ in the human brain, and if so, could this lowering be too little, too late? These central questions in research on AD are being urgently addressed.

          Abstract

          Evidence suggests that an imbalance between production and clearance of amyloid-beta is an early, invariant feature of Alzheimer disease that drives its neuronal and glial pathology and precedes cognitive symptoms. So why are we still unable to slow cognitive decline with anti-amyloid therapies?

          Related collections

          Most cited references85

          • Record: found
          • Abstract: found
          • Article: not found

          A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

          Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            The amyloid hypothesis of Alzheimer's disease at 25 years

            Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

              The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
                Bookmark

                Author and article information

                Journal
                PLoS Biol
                PLoS Biol
                plos
                PLoS Biology
                Public Library of Science (San Francisco, CA USA )
                1544-9173
                1545-7885
                21 July 2022
                July 2022
                21 July 2022
                : 20
                : 7
                : e3001694
                Affiliations
                [1 ] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
                [2 ] Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany
                [3 ] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
                [4 ] Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
                Author notes

                CH and DJS have read the journal’s policy and the authors of this manuscript have the following competing interests. CH collaborates with Denali Therapeutics on microglia related therapeutic strategies. CH is chief advisor of ISAR Bioscience and a member of the advisory board of AviadoBio. CH once joined a review panel of Biogen, which did not include Aducanumab. DJS is a director and consultant to Prothena Biosciences.

                Author information
                https://orcid.org/0000-0002-4869-1627
                https://orcid.org/0000-0001-8846-9767
                Article
                PBIOLOGY-D-22-00265
                10.1371/journal.pbio.3001694
                9302755
                35862308
                c3eb7a9c-c060-4268-ba1c-9334414682fa
                © 2022 Haass, Selkoe

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Page count
                Figures: 3, Tables: 1, Pages: 15
                Funding
                Funded by: DFG
                Award ID: EXC 2145 SyNergy – ID 390857198
                Award Recipient :
                Funded by: DFG
                Award ID: HA1737/16-1
                Award Recipient :
                Funded by: NIH
                Award ID: RF1 AG006173
                Award Recipient :
                Funded by: NIH
                Award ID: P01 AG015379
                Award Recipient :
                Funded by: David APP Fund at BWH
                Award Recipient :
                CH is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and a Koselleck Project HA1737/16-1. DS is supported by the following grants: RF1 AG006173 Aging in the Brain: Role of the Fibrous Proteins; P01 AG015379 Presenilin Biology and The Mechanism of Alzheimer's Disease and the Davis APP Fund at BWH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Unsolved Mystery
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Dementia
                Alzheimer's Disease
                Medicine and Health Sciences
                Neurology
                Dementia
                Alzheimer's Disease
                Medicine and Health Sciences
                Medical Conditions
                Neurodegenerative Diseases
                Alzheimer's Disease
                Medicine and Health Sciences
                Neurology
                Neurodegenerative Diseases
                Alzheimer's Disease
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Amyloid Plaques
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Glial Cells
                Microglial Cells
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Research and Analysis Methods
                Imaging Techniques
                Neuroimaging
                Positron Emission Tomography
                Biology and Life Sciences
                Neuroscience
                Neuroimaging
                Positron Emission Tomography
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Tomography
                Positron Emission Tomography
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Tomography
                Positron Emission Tomography
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Tomography
                Positron Emission Tomography
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognitive Neuroscience
                Cognitive Neurology
                Cognitive Impairment
                Biology and Life Sciences
                Neuroscience
                Cognitive Neuroscience
                Cognitive Neurology
                Cognitive Impairment
                Medicine and Health Sciences
                Neurology
                Cognitive Neurology
                Cognitive Impairment
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Trials
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
                Clinical Trials
                Research and Analysis Methods
                Clinical Trials
                Biology and Life Sciences
                Genetics
                Human Genetics

                Life sciences
                Life sciences

                Comments

                Comment on this article