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      Multimorbidity burden and dementia risk in older adults: The role of inflammation and genetics

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          Abstract

          Introduction

          We investigate dementia risk in older adults with different disease patterns and explore the role of inflammation and apolipoprotein E ( APOE) genotype.

          Methods

          A total of 2,478 dementia‐free participants with two or more chronic diseases (ie, multimorbidity) part of the Swedish National study on Aging and Care in Kungsholmen (SNAC‐K) were grouped according to their multimorbidity patterns and followed to detect clinical dementia. The potential modifier effect of C‐reactive protein (CRP) and apolipoprotein E ( APOE) genotype was tested through stratified analyses.

          Results

          People with neuropsychiatric, cardiovascular, and sensory impairment/cancer multimorbidity had increased hazards for dementia compared to the unspecific (Hazard ration (HR) 1.66, 95% confidence interval [CI] 1.13‐2.42; 1.61, 95% CI 1.17‐2.29; 1.32, 95% CI 1.10‐1.71, respectively). Despite the lack of statistically significant interaction, high CRP increased dementia risk within these patterns, and being APOE ε4 carriers heightened dementia risk for neuropsychiatric and cardiovascular multimorbidity.

          Discussion

          Individuals with neuropsychiatric, cardiovascular, and sensory impairment/cancer patterns are at increased risk for dementia and APOE ε4, and inflammation may further increase the risk. Identifying such high‐risk groups might allow tailored interventions for dementia prevention.

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          Most cited references52

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          Dementia prevention, intervention, and care

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            Chronic inflammation in the etiology of disease across the life span

            Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.
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              Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

              Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.
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                Author and article information

                Contributors
                giulia.grande@ki.se
                Journal
                Alzheimers Dement
                Alzheimers Dement
                10.1002/(ISSN)1552-5279
                ALZ
                Alzheimer's & Dementia
                John Wiley and Sons Inc. (Hoboken )
                1552-5260
                1552-5279
                06 January 2021
                May 2021
                : 17
                : 5 ( doiID: 10.1002/alz.v17.5 )
                : 768-776
                Affiliations
                [ 1 ] Aging Research Center Department of Neurobiology, Care Sciences and Society Karolinska Institutet and Stockholm University Stockholm Sweden
                [ 2 ] Department of Clinical and Experimental Sciences University of Brescia Brescia Italy
                [ 3 ] Centro di Medicina dell'Invecchiamento IRCCS Fondazione Policlinico “A. Gemelli” and Università Cattolica del Sacro Cuore Rome Italy
                [ 4 ] Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol) Barcelona Spain
                [ 5 ] Universitat Autònoma de Barcelona Bellaterra (Cerdanyola del Vallès) Spain
                [ 6 ] Department of Information Engineering University of Brescia Brescia Italy
                [ 7 ] Stockholm Gerontology Research Center Stockholm Sweden
                Author notes
                [*] [* ] Correspondence

                Giulia Grande, Aging Research Center, Karolinska Institutet, Tomtebodavägen 18A, 171 65 Solna, Sweden.

                Email: giulia.grande@ 123456ki.se

                [*]

                Contributed equally

                Article
                ALZ12237
                10.1002/alz.12237
                8247430
                33403740
                17d538f9-833f-456a-9f4f-4ce2f926594f
                © 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 20 October 2020
                : 16 June 2020
                : 24 October 2020
                Page count
                Figures: 1, Tables: 2, Pages: 9, Words: 6407
                Funding
                Funded by: Swedish National study on Aging and Care
                Funded by: Ministry of Health and Social Affairs , open-funder-registry 10.13039/501100005348;
                Funded by: Swedish Research Council , open-funder-registry 10.13039/501100004359;
                Award ID: 2016‐00981
                Funded by: Swedish Research Council for Health, Working Life and Welfare , open-funder-registry 10.13039/501100006636;
                Award ID: 2017‐01764
                Funded by: Italian Ministry of Health
                Award ID: PE‐2016‐02364885
                Categories
                Featured Article
                Featured Articles
                Custom metadata
                2.0
                May 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:01.07.2021

                dementia,genetics,inflammation,multimorbidity patterns
                dementia, genetics, inflammation, multimorbidity patterns

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