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      Longitudinal Maintenance of Cognitive Health in Centenarians in the 100-plus Study

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          Key Points

          Question

          Is it possible to identify centenarians who escape cognitive decline?

          Findings

          In this cohort study of 340 centenarians, most individuals who scored 26 or higher on the Mini-Mental State Examination at study inclusion maintained this level of performance for at least 2 years of follow-up, despite having risk factors associated with cognitive decline. This group represents less than 10% of the centenarians in the Dutch population.

          Meaning

          Using the Mini-Mental State Examination, this study identified a small subgroup of centenarians who maintained high levels of cognitive functioning and showed resilience against risk factors associated with cognitive decline.

          Abstract

          This cohort study of Dutch centenarians examines individuals who escape cognitive decline until extreme ages and investigates the prevalence of risk factors associated with cognitive decline.

          Abstract

          Importance

          Some individuals who reach ages beyond 100 years in good cognitive health may be resilient against risk factors associated with cognitive decline. Exploring the processes underlying resilience may contribute to the development of therapeutic strategies that help to maintain cognitive health while aging.

          Objective

          To identify individuals who escape cognitive decline until extreme ages and to investigate the prevalence of associated risk factors.

          Design, Setting, and Participants

          The 100-plus Study is a prospective observational cohort study of community-based Dutch centenarians enrolled between 2013 and 2019 who were visited annually until death or until participation was no longer possible. The centenarians self-reported their cognitive health, as confirmed by a proxy. Of the 1023 centenarians approached for study inclusion, 340 fulfilled the study criteria and were included in analyses. Data analysis was performed from April 2019 to December 2019.

          Main Outcomes and Measures

          Cognition was assessed using the Mini-Mental State Examination (MMSE). To identify centenarians who escape cognitive decline, this study investigated the association of baseline cognition with survivorship and cognitive trajectories for at least 2 years of follow-up using linear mixed models, adjusted for sex, age, and education. This study investigated the prevalence of apolipoprotein E ( APOE) genotypes and cardiovascular disease as risk factors associated with cognitive decline.

          Results

          At baseline, the median age of 340 centenarians was 100.5 years (range, 100.0-108.2 years); 245 participants (72.1%) were female. The maximum survival estimate plateaued at 82% per year (95% CI, 77% to 87%) across centenarians who scored 26 to 30 points on the baseline MMSE (hazard ratio, 0.56; 95% CI, 0.42 to 0.75; P < .001), suggesting that an MMSE score of 26 or higher is representative of both cognitive and physical health. Among the 79 centenarians who were followed up for 2 years or longer, those with baseline MMSE score less than 26 experienced a decline in MMSE score of 1.68 points per year (95% CI, −2.45 to −0.92 points per year; P = .02), whereas centenarians with MMSE scores of 26 or higher at baseline experienced a decline of 0.71 point per year (95% CI, −1.08 to −0.35 points per year). For 73% of the centenarians with baseline MMSE scores of 26 or higher, no cognitive changes were observed, which often extended to ensuing years or until death. It is estimated that this group is representative of less than 10% of Dutch centenarians. In this group, 18.6% carried at least 1 APOE-ε4 allele, compared with 5.6% of the centenarians with lower and/or declining cognitive performance.

          Conclusions and Relevance

          Most centenarians who scored 26 or higher on the MMSE at baseline maintained high levels of cognitive performance for at least 2 years, in some cases despite the presence of risk factors associated with cognitive decline. Investigation of this group might reveal the processes underlying resilience against risk factors associated with cognitive decline.

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          Most cited references43

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          Resistance to autosomal dominant Alzheimer’s in an APOE3 -Christchurch homozygote: a case report

          We identified a PSEN1 mutation carrier from the world’s largest autosomal dominant Alzheimer’s disease kindred who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. She had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid, and limited tau/tangle and neurodegenerative measurements. Our findings have implications for APOE’s role in the pathogenesis, treatment, and prevention of Alzheimer’s disease.
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            A major role for cardiovascular burden in age-related cognitive decline.

            The incidence of dementia and cardiovascular disease (CVD) increases with age. Current evidence supports the role for both atherosclerosis and arteriosclerosis as a common pathophysiological ground for the heart-brain connection in ageing. Cognitive decline and CVDs share many vascular risk factors (VRFs) such as smoking, hypertension, and diabetes mellitus; furthermore, CVDs can contribute to cognitive decline by causing cerebral hypoperfusion, hypoxia, emboli, or infarcts. Mixed dementia, resulting from both cerebrovascular lesions and neurodegeneration, accounts for the majority of dementia cases among very old individuals (≥75 years). An accumulation of multiple VRFs, especially in middle age (40-59 years of age), can substantially increase dementia risk. The suggested declining trend in dementia risk, occurring in parallel with the decreasing incidence of cardiovascular events in high-income countries, supports the role of cardiovascular burden in dementia. Accordingly, strategies to promote cardiovascular health, especially if implemented from early life, might help to delay the onset of dementia. In this Review, we discuss the literature investigating the association of cardiovascular burden with cognitive decline and dementia over the life-course.
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              Trajectories of normal cognitive aging.

              Although sensitive detection of pathological cognitive aging requires accurate information about the trajectory of normal cognitive aging, prior research has revealed inconsistent patterns of age-cognition relations with cross-sectional and longitudinal comparisons. Age trends in four cognitive domains were compared in over 5,000 adults with cross-sectional data, and in almost 1,600 adults with three-occasion longitudinal data. Quasi-longitudinal comparisons, which are similar to cross-sectional comparisons in that there is no prior test experience, and are similar to longitudinal comparisons in that the participants are from the same birth cohorts, were also reported. The age trends in quasi-longitudinal comparisons more closely resembled those in cross-sectional comparisons than those in longitudinal comparisons, which suggests that, at least up until about age 65, age-cognition relations in longitudinal comparisons are distorted by prior test experience. Results from cross-sectional and quasi-longitudinal comparisons, which can be assumed to have minimal test experience effects, imply that normal cognitive aging is characterized by nearly linear declines from early adulthood in speed, and accelerating declines in memory and reasoning. However, vocabulary knowledge increased until the decade of the 60’s in all three types of comparisons.
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                26 February 2020
                February 2020
                26 February 2020
                : 3
                : 2
                : e200094
                Affiliations
                [1 ]Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
                [2 ]Department of Clinical Psychology, Neuropsychology, and Developmental Psychology, Faculty of Behavioural and Movement Sciences, Vrije Universiteit, Amsterdam, the Netherlands
                [3 ]Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
                Author notes
                Article Information
                Accepted for Publication: January 6, 2020.
                Published: February 26, 2020. doi:10.1001/jamanetworkopen.2020.0094
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Beker N et al. JAMA Network Open.
                Corresponding Author: Henne Holstege, PhD, Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, De Boelelaan 1118, Amsterdam 1081 HZ, the Netherlands ( h.holstege@ 123456amsterdamumc.nl ).
                Author Contributions: Dr Holstege and Ms Beker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Beker, Sikkes, Hulsman, van der Lee, Scheltens, Holstege.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Beker, Sikkes, Hulsman, van der Lee, Scheltens, Holstege.
                Critical revision of the manuscript for important intellectual content: Beker, Sikkes, Tesi, van der Lee, Scheltens, Holstege.
                Statistical analysis: Beker, Hulsman, Tesi, van der Lee.
                Obtained funding: Scheltens, Holstege.
                Administrative, technical, or material support: Tesi, Scheltens, Holstege.
                Supervision: Sikkes, van der Lee, Scheltens, Holstege.
                Conflict of Interest Disclosures: Dr Sikkes reported receiving grants from Zon-MW during the conduct of the study. No other disclosures were reported.
                Funding/Support: This work was supported by Stichting Alzheimer Nederland (grant WE09.2014-03), Stichting Dioraphte (grant VSM 14 04 1402), and Stichting VUmc Fonds. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience.
                Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Additional Contributions: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relatives. We acknowledge the people who visited and/or recruited the centenarians. We thank Michel Poulain, PhD (UCLouvain, Louvain-la-Neuve, Belgium; and Tallinn University, Tallinn, Estonia), and Rik Ossenkoppele, PhD, Linda Wesselman, MSc, Roos Jutten, PhD, Mark Dubbelman, MSc, Josephine Drijver, MSc, Quirien Oort, MSc, and Merike Verrijp, MSc (all from Amsterdam UMC, Amsterdam, the Netherlands), for reading the manuscript and advising on the interpretation of the results. None of these individuals was compensated for their contribution.
                Article
                zoi200010
                10.1001/jamanetworkopen.2020.0094
                7137688
                32101309
                6740642e-5493-4e26-8a5c-0b329bc5552f
                Copyright 2020 Beker N et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 29 August 2019
                : 6 January 2020
                Categories
                Research
                Original Investigation
                Online Only
                Neurology

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