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      The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

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          Abstract

          Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

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          Most cited references 12

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          Amyloid-β Receptors: The Good, the Bad, and the Prion Protein*

          Several different receptor proteins have been identified that bind monomeric, oligomeric, or fibrillar forms of amyloid-β (Aβ). “Good” receptors internalize Aβ or promote its transcytosis out of the brain, whereas “bad” receptors bind oligomeric forms of Aβ that are largely responsible for the synapticloss, memory impairments, and neurotoxicity that underlie Alzheimer disease. The prion protein both removes Aβ from the brain and transduces the toxic actions of Aβ. The clustering of distinct receptors in cell surface signaling platforms likely underlies the actions of distinct oligomeric species of Aβ. These Aβ receptor-signaling platforms provide opportunities for therapeutic intervention in Alzheimer disease.
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            Screening for predementia AD: time-dependent operating characteristics of episodic memory tests.

            Data from the Einstein Aging Study (EAS) were used to prospectively evaluate the free recall score from the free and cued selective reminding test (FCSRT-FR) and logical memory I immediate recall (LM-IR) subtest of the Wechsler memory scale-revised for prediction of incident Alzheimer disease (AD) dementia among individuals from a community-based cohort with memory complaints. Analyses included 854 participants, age ≥70 years, who initially had no dementia, and had memory complaints. Clinic evaluations were completed annually and AD dementia was diagnosed using standard criteria (n = 86 cases; average follow-up 4.1 years). Time-dependent receiver operating characteristic analysis was used to evaluate the prognostic ability of FCSRT-FR and LM-IR for incident AD over various durations of follow-up. For identifying those with memory complaints who will develop incident AD dementia over 2-4 years, the FCSRT-FR had better operating characteristics than LM-IR. APOE ε4 status, age, and education did not affect cut points; however, positive predictive values were higher among APOE ε4-positive individuals. For follow-up intervals of 2-4 years, the FCSRT-FR is more predictive than the LM-IR for identifying individuals with memory complaints who will develop incident AD. APOE ε4 status improves positive predictive value, but does not affect the choice of optimal cuts.
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              The therapeutics of Alzheimer's disease: where we stand and where we are heading.

               Dennis Selkoe (2013)
              Few diagnoses in modern medicine evoke more apprehension in patients and their families than Alzheimer disease (AD). Defined as a clinical and pathological entity a century ago, the disorder only came under intense molecular scrutiny in the mid-1980s. Genetic, histopathological, biochemical, and animal modeling studies have combined to provide evidence that the disease may begin with an imbalance between the production and clearance of the self-aggregating amyloid β protein (Aβ) in brain regions serving memory and cognition. This concept has been furthered by recent analyses in humans of cerebrospinal fluid and neuroimaging biomarkers that suggest an approximate sequence of AD-type brain alterations beginning >2 decades before the onset of dementia. Although the Aβ hypothesis of Alzheimer causation does not explain all features of this multifactorial syndrome, experimental agents that lower or neutralize Aβ have become the major focus of therapeutic research. Several clinical trials in mild-to-moderate AD have not met standard cognitive and functional endpoints, but there were important shortcomings in the agent and/or the trial design in each case. Based on the lessons learned, the field has moved on to test potentially disease-modifying agents in mild AD patients or via secondary prevention in presymptomatic subjects bearing amyloid plaques. Immunotherapeutic agents are receiving the most study, but other antiamyloid strategies and, importantly, nonamyloid targets such as tau and neuroinflammation are of great interest. The pace of recent developments augurs well for 1 or more experimental agents being shown to slow cognitive decline without major side effects. However, research funding from all sources will need to increase dramatically and soon to stave off the approaching tsunami of AD.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Nature
                1476-4687
                0028-0836
                September 01 2016
                : 537
                : 7618
                Affiliations
                [1 ] Biogen, Cambridge, Massachusetts 02142, USA.
                [2 ] Neurimmune, Schlieren-Zurich 8952, Switzerland.
                [3 ] Butler Hospital, Providence, Rhode Island 02906, USA.
                [4 ] Institute for Regenerative Medicine, University of Zurich, Zurich 8952, Switzerland.
                Article
                nature19323
                10.1038/nature19323
                27582220
                95fcf159-9593-410a-99f4-4a0abdbf4bed

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