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      Alzheimer's disease progression and risk factors: A standardized comparison between six large data sets

      research-article
      a , , a , a , a , b , c , d , a , e , a , Australian Imaging Biomarkers and Lifestyle flagship study of ageing 2 , Predictors of Cognitive Decline Among Normal Individuals (BIOCARD) study 3 , Add Neuro Med Consortium
      Alzheimer's & Dementia : Translational Research & Clinical Interventions
      Elsevier
      Epidemiology, Dementia, Statistical analysis, Mild cognitive impairment, Mixed regression, Modeling

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          Abstract

          There exist a large number of cohort studies that have been used to identify genetic and biological risk factors for developing Alzheimer's disease (AD). However, there is a disagreement between studies as to how strongly these risk factors affect the rate of progression through diagnostic groups toward AD. We have calculated the probability of transitioning through diagnostic groups in six studies and considered how uncertainty around the strength of the effect of these risk factors affects estimates of the distribution of individuals in each diagnostic group in an AD clinical trial simulator. In this work, we identify the optimal choice of widely collected variables for comparing data sets and calculating probabilities of progression toward AD. We use the estimated transition probabilities to inform stochastic simulations of AD progression that are based on a Markov model and compare predicted incidence rates to those in a community-based study, the Cardiovascular Health Study.

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          Most cited references14

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          Quantification of biological aging in young adults.

          Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their "biological aging" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.
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            Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions.

            The DNA methylation levels of certain CpG sites are thought to reflect the pace of human aging. Here, we developed a robust predictor of mouse biological age based on 90 CpG sites derived from partial blood DNA methylation profiles. The resulting clock correctly determines the age of mouse cohorts, detects the longevity effects of calorie restriction and gene knockouts, and reports rejuvenation of fibroblast-derived iPSCs. The data show that mammalian DNA methylomes are characterized by CpG sites that may represent the organism's biological age. They are scattered across the genome, they are distinct in human and mouse, and their methylation gradually changes with age. The clock derived from these sites represents a biomarker of aging and can be used to determine the biological age of organisms and evaluate interventions that alter the rate of aging.
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              • Record: found
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              • Article: not found

              Why do so many clinical trials of therapies for Alzheimer's disease fail?

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                Author and article information

                Contributors
                Journal
                Alzheimers Dement (N Y)
                Alzheimers Dement (N Y)
                Alzheimer's & Dementia : Translational Research & Clinical Interventions
                Elsevier
                2352-8737
                03 October 2019
                2019
                03 October 2019
                : 5
                : 515-523
                Affiliations
                [a ]Department of Infectious Disease Epidemiology, School of Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom
                [b ]University of Melbourne Academic Unit for Psychiatry of Old Age, St George's Hospital, Kew, Victoria, Australia
                [c ]National Ageing Research Institute, Parkville, Victoria, Australia
                [d ]Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
                [e ]Janssen Prevention Center, Leiden, the Netherlands
                Author notes
                []Corresponding author. Tel.: +44 (0) 2075943286. s.evans@ 123456imperial.ac.uk
                [1]

                Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database ( adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

                [2]

                Data used in the preparation of this article were obtained from the Australian Imaging Biomarkers and Lifestyle flagship study of aging (AIBL) funded by the Commonwealth Scientific and Industrial Research Organisation (CSIRO), which was made available at the ADNI database ( www.loni.usc.edu/ADNI). The AIBL researchers contributed data but did not participate in analysis or writing of this report. AIBL researchers are listed at www.aibl.csiro.au.

                [3]

                Data used in the preparation of this article were obtained from The Predictors of Cognitive Decline Among Normal Individuals (BIOCARD) funded by grants from the National Institutes of Health and made available at http://www.biocard-se.org. The BIOCARD researchers contributed data but did not participate in analysis or writing of this report. The BIOCARD Study consists of 7 Cores, and members are listed at http://www.biocard-se.org.

                Article
                S2352-8737(19)30019-8
                10.1016/j.trci.2019.04.005
                6804515
                da8f8ad7-46d4-4ffd-904b-4f0a2d591fe1
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                epidemiology,dementia,statistical analysis,mild cognitive impairment,mixed regression,modeling

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