Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network
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    Original Investigation
    January 15, 2021

    Association of Cognitive Function Trajectories in Centenarians With Postmortem Neuropathology, Physical Health, and Other Risk Factors for Cognitive Decline

    Author Affiliations
    • 1Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
    • 2Center for Neurogenomics and Cognitive Research, Department of Molecular and Cellular Neuroscience, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
    • 3Department of Pathology, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, the Netherlands
    • 4Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
    • 5Amsterdam Public Health Research Institute, Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
    • 6Brain & Cognition, Department of Psychology, University of Amsterdam, Amsterdam, the Netherlands
    • 7Department of Clinical Psychology, Neuropsychology and Developmental Psychology, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
    JAMA Netw Open. 2021;4(1):e2031654. doi:10.1001/jamanetworkopen.2020.31654
    Key Points

    Question  Are cognitively healthy centenarians resilient against further cognitive decline?

    Findings  In this cohort study of 330 self-reported cognitively healthy centenarians, cognitive trajectories revealed only a slight decline in memory functioning, while other domains remained stable over time. Centenarians maintained high levels of cognitive performance despite being exposed to varying levels of risk factors of cognitive decline, including postmortem Alzheimer disease–associated neuropathologies.

    Meaning  These findings indicate that prolonged maintenance of cognitive functioning may be supported by mechanisms underlying resilience against risk factors of cognitive decline.


    Importance  Understanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging.

    Objective  To investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)–associated neuropathology.

    Design, Setting, and Participants  This cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020.

    Exposures  Age, sex, APOE ε genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-β, neurofibrillary tangles, and neuritic plaques).

    Main Outcomes and Measures  In annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology.

    Results  Of the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (β, −0.10 SD per year; 95% CI, −0.14 to −0.05 SD; P < .001). Cognitive performance was associated with factors of physical health (eg, higher Barthel index: β, 0.37 SD per year; 95% CI, 0.24-0.49; P < .001) and cognitive reserve (eg, higher education: β, 0.41 SD per year; 95% CI, 0.29-0.53; P < .001), but none of these factors were associated with the rate of decline. Neuropathological reports were available for 44 participants. While centenarian brains revealed varying loads of postmortem neuropathological hallmarks of AD, this was not associated with cognitive performance or rate of decline.

    Conclusions and Relevance  While we observed a slight vulnerability for decline in memory function, centenarians maintained high levels of performance in all other investigated cognitive domains for up to 4 years despite the presence of risk factors of cognitive decline. These findings suggest that mechanisms of resilience may underlie the prolongation of cognitive health until exceptional ages.