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      Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

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          Abstract

          Alzheimer’s disease (AD) is a progressive neurodegenerative disease and accounts for most cases of dementia. The prevalence of AD has increased in the current rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. Finding novel treatments for AD has become urgent. In this paper, we reviewed novel therapeutic approaches in five categories: anti-amyloid therapy, anti-tau therapy, anti-neuroinflammatory therapy, neuroprotective agents including N-methyl-D-aspartate (NMDA) receptor modulators, and brain stimulation. The trend of therapeutic development is shifting from a single pathological target to a more complex mechanism, such as the neuroinflammatory and neurodegenerative processes. While drug repositioning may accelerate pharmacological development, non-pharmacological interventions, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential for clinical application. In the future, it is possible for physicians to choose appropriate interventions individually on the basis of precision medicine.

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          2020 Alzheimer's disease facts and figures

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            Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

            Summary Background The number of individuals living with dementia is increasing, negatively affecting families, communities, and health-care systems around the world. A successful response to these challenges requires an accurate understanding of the dementia disease burden. We aimed to present the first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, and highlight the most important messages for clinicians and neurologists. Methods GBD 2016 obtained data on dementia from vital registration systems, published scientific literature and surveys, and data from health-service encounters on deaths, excess mortality, prevalence, and incidence from 195 countries and territories from 1990 to 2016, through systematic review and additional data-seeking efforts. To correct for differences in cause of death coding across time and locations, we modelled mortality due to dementia using prevalence data and estimates of excess mortality derived from countries that were most likely to code deaths to dementia relative to prevalence. Data were analysed by standardised methods to estimate deaths, prevalence, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs; computed as the sum of YLLs and YLDs), and the fractions of these metrics that were attributable to four risk factors that met GBD criteria for assessment (high body-mass index [BMI], high fasting plasma glucose, smoking, and a diet high in sugar-sweetened beverages). Findings In 2016, the global number of individuals who lived with dementia was 43·8 million (95% uncertainty interval [UI] 37·8–51·0), increased from 20.2 million (17·4–23·5) in 1990. This increase of 117% (95% UI 114–121) contrasted with a minor increase in age-standardised prevalence of 1·7% (1·0–2·4), from 701 cases (95% UI 602–815) per 100 000 population in 1990 to 712 cases (614–828) per 100 000 population in 2016. More women than men had dementia in 2016 (27·0 million, 95% UI 23·3–31·4, vs 16.8 million, 14.4–19.6), and dementia was the fifth leading cause of death globally, accounting for 2·4 million (95% UI 2·1–2·8) deaths. Overall, 28·8 million (95% UI 24·5–34·0) DALYs were attributed to dementia; 6·4 million (95% UI 3·4–10·5) of these could be attributed to the modifiable GBD risk factors of high BMI, high fasting plasma glucose, smoking, and a high intake of sugar-sweetened beverages. Interpretation The global number of people living with dementia more than doubled from 1990 to 2016, mainly due to increases in population ageing and growth. Although differences in coding for causes of death and the heterogeneity in case-ascertainment methods constitute major challenges to the estimation of the burden of dementia, future analyses should improve on the methods for the correction of these biases. Until breakthroughs are made in prevention or curative treatment, dementia will constitute an increasing challenge to health-care systems worldwide. Funding Bill & Melinda Gates Foundation.
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              Alzheimer's disease.

              Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have decreased as a result of better vascular care and improved brain health. Alzheimer's disease, the most prevalent cause of dementia, is still defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective, and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid β42, and tau proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid β oligomers and synaptic markers. MRI and fluorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimer's disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-effectiveness remain to be established. Tau PET might offer new insights and be of great help in differential diagnosis and selection of patients for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving increasingly into the earliest phase of disease. Preclinical Alzheimer's disease is defined as biomarker evidence of Alzheimer's pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have been identified as a useful population in whom to look for preclinical Alzheimer's disease. Moderately positive results for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim results for lowering amyloid in pre-dementia Alzheimer's disease suggest that, ultimately, there will be a future in which specific anti-Alzheimer's therapy will be combined with lifestyle interventions targeting general brain health to jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimer's research.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                30 July 2021
                August 2021
                : 22
                : 15
                : 8208
                Affiliations
                [1 ]Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; mp9596@ 123456cgmh.org.tw
                [2 ]Department of Psychiatry and Brain Disease Research Center, China Medical University Hospital, Taichung 40402, Taiwan
                [3 ]Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
                [4 ]Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung 41354, Taiwan
                [5 ]School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
                Author notes
                [* ]Correspondence: hylane@ 123456gmail.com (H.-Y.L.); cyndi36@ 123456gmail.com (C.-H.L.); Tel.: +886-921-067-260 (H.-Y.L.); +886-7-7317123 (ext. 8753) (C.-H.L.); Fax: +886-4-2236-1042 (H.-Y.L.); +886-7-7326817 (C.-H.L.)
                Author information
                https://orcid.org/0000-0003-2162-8174
                Article
                ijms-22-08208
                10.3390/ijms22158208
                8348485
                34360973
                7fc52a13-6921-45e4-bdf5-297407b8cf3e
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 25 June 2021
                : 27 July 2021
                Categories
                Review

                Molecular biology
                alzheimer’s disease,amyloid,tau,nmda,neuroinflammation,neuroprotection,brain stimulation,rtms,tdcs,precision medicine

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