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.