Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

Clinicians and researchers have shown increasing interest in frailty. Yet, there is still considerable uncertainty regarding the concept and its definition. In this article, we present perspectives on key issues and controversies discussed by scientists from 13 different countries, representing a diverse range of disciplines, at the 2006 Second International Working Meeting on Frailty and Aging. The following fundamental questions are discussed: What is the distinction, if any, between frailty and aging? What is its relationship with chronic disease? Is frailty a syndrome or a series of age-related impairments that predict adverse outcomes? What are the critical domains in its operational definition? Is frailty a useful concept? The implications of different models and approaches are examined. Although consensus has yet to be attained, work accomplished to date has opened exciting new horizons. The article concludes with suggested directions for future research.

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There is agreement on the usefulness of defining frailty in clinical settings as well as on its main dimensions. However, additional research is needed before an operative definition of frailty can be established.

Gait speed is a simple and effective test that may identify a subset of vulnerable elderly patients at incrementally higher risk of mortality and major morbidity after cardiac surgery.

An operational definition of frailty is important for clinical care, research, and policy planning. The literature on the clinical definitions, screening tools, and severity measures of frailty were systematically reviewed as part of the Canadian Initiative on Frailty and Aging. Searches of MEDLINE from 1997 to 2009 were conducted, and reference lists of retrieved articles were pearled, to identify articles published in English and French on the identification of frailty in community-dwelling people aged 65 and older. Two independent reviewers extracted descriptive information on study populations, frailty criteria, and outcomes from the selected papers, and quality rankings were assigned. Of 4,334 articles retrieved from the searches and 70 articles retrieved from the pearling, 22 met study inclusion criteria. In the 22 articles, physical function, gait speed, and cognition were the most commonly used identifying components of frailty, and death, disability, and institutionalization were common outcomes. The prevalence of frailty ranged from 5% to 58%. Despite significant work over the past decade, a clear consensus definition of frailty does not emerge from the literature. The definition and outcomes that best suit the unique needs of the researchers, clinicians, or policy-makers conducting the screening determine the choice of a screening tool for frailty. Important areas for further research include whether disability should be considered a component or an outcome of frailty. In addition, the role of cognitive and mood elements in the frailty construct requires further clarification.

Fitness and frailty form a continuum and predict survival. Exercise influences survival, even in old age. Relative fitness and frailty can be determined quickly in a clinical setting, are potentially useful markers of the risk for adverse health outcomes, and add value to traditional medical assessments that focus on diagnoses.

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