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      Targeting the M1 muscarinic acetylcholine receptor in Alzheimer’s disease

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          Abstract

          Alzheimer’s disease (AD) remains a major cause of morbidity and mortality worldwide, and despite extensive research, only a few drugs are available for management of the disease. One strategy has been to up-regulate cholinergic neurotransmission to improve cognitive function, but this approach has dose-limiting adverse effects. To avoid these adverse effects, new drugs that target specific receptor subtypes of the cholinergic system are needed, and the M1 subtype of muscarinic acetylcholine receptor (M1-mAChR) has been shown to be a good target for this approach. By using several strategies, M1-mAChR ligands have been developed and trialled in preclinical animal models and in human studies, with varying degrees of success. This article reviews the different approaches to targeting the M1-mAChR in AD and discusses the advantages and limitations of these strategies. The factors to consider in targeting the M1-mAChR in AD are also discussed.

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          2021 Alzheimer's disease facts and figures

          (2021)
          This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality and morbidity, use and costs of care, and the overall impact on caregivers and society. The Special Report discusses the challenges of providing equitable health care for people with dementia in the United States. An estimated 6.2 million Americans age 65 and older are living with Alzheimer's dementia today. This number could grow to 13.8 million by 2060 barring the development of medical breakthroughs to prevent, slow or cure AD. Official death certificates recorded 121,499 deaths from AD in 2019, the latest year for which data are available, making Alzheimer's the sixth-leading cause of death in the United States and the fifth-leading cause of death among Americans age 65 and older. Between 2000 and 2019, deaths from stroke, heart disease and HIV decreased, whereas reported deaths from AD increased more than 145%. This trajectory of deaths from AD was likely exacerbated in 2020 by the COVID-19 pandemic. More than 11 million family members and other unpaid caregivers provided an estimated 15.3 billion hours of care to people with Alzheimer's or other dementias in 2020. These figures reflect a decline in the number of caregivers compared with a decade earlier, as well as an increase in the amount of care provided by each remaining caregiver. Unpaid dementia caregiving was valued at $256.7 billion in 2020. Its costs, however, extend to family caregivers' increased risk for emotional distress and negative mental and physical health outcomes - costs that have been aggravated by COVID-19. Average per-person Medicare payments for services to beneficiaries age 65 and older with AD or other dementias are more than three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 23 times as great. Total payments in 2021 for health care, long-term care and hospice services for people age 65 and older with dementia are estimated to be $355 billion. Despite years of efforts to make health care more equitable in the United States, racial and ethnic disparities remain - both in terms of health disparities, which involve differences in the burden of illness, and health care disparities, which involve differences in the ability to use health care services. Blacks, Hispanics, Asian Americans and Native Americans continue to have a higher burden of illness and lower access to health care compared with Whites. Such disparities, which have become more apparent during COVID-19, extend to dementia care. Surveys commissioned by the Alzheimer's Association recently shed new light on the role of discrimination in dementia care, the varying levels of trust between racial and ethnic groups in medical research, and the differences between groups in their levels of concern about and awareness of Alzheimer's disease. These findings emphasize the need to increase racial and ethnic diversity in both the dementia care workforce and in Alzheimer's clinical trials.
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            The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.

            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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              Donanemab in Early Alzheimer’s Disease

              A hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer's disease.
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                Author and article information

                Contributors
                Journal
                Neuronal Signal
                Neuronal Signal
                ns
                Neuronal Signaling
                Portland Press Ltd.
                2059-6553
                April 2022
                21 April 2022
                : 6
                : 1
                : NS20210004
                Affiliations
                The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
                Author notes
                Correspondence: Louis Dwomoh ( louis.dwomoh@ 123456glasgow.ac.uk ) or Andrew B. Tobin ( andrew.tobin@ 123456glasgow.ac.uk )
                Author information
                https://orcid.org/0000-0001-7024-6450
                Article
                NS20210004
                10.1042/NS20210004
                9069568
                35571495
                c09af11c-a115-4257-8c6c-d090d4ef6a4b
                © 2022 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 02 February 2022
                : 01 April 2022
                : 04 April 2022
                : 05 April 2022
                Page count
                Pages: 20
                Categories
                Neuroscience
                Therapeutics & Molecular Medicine
                Review Articles

                acetylcholine,allosteric regulation,alzheimer's disease,muscarinic receptor,orthosteric

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