Abstract

Aging occurs as a series of small steps, first causing cellular damage and then affecting tissues and organs. This is also true in the brain. Frailty, a state of increased risk due to accelerated deficit accumulation, is robustly a risk factor for cognitive impairment. Community-based autopsy studies show that frail individuals have brains that show multiple deficits without necessarily demonstrating cognitive impairment. These facts cast a new light on the growing number of risk factors for cognitive impairment, suggesting that, on a population basis, most health deficits can be associated with late-life cognitive impairment. The systems mechanism by which things that are bad for the body are likely to be bad for the brain can be understood like this: the burden of health deficits anywhere indicates impaired ability to withstand or repair endogenous and environmental damage. This in turn makes additional damage more likely. If true, this suggests that a life course approach to preventing cognitive impairment is desirable. Furthermore, conducting studies in highly selected, younger, healthier individuals to provide ‘proof of concept’ information is now common. This strategy might exclude the very circumstances that are required for disease expression in the people in whom dementia chiefly occurs (that is, older adults who are often in poor health).

Highlights

  • Until death intervenes, aging in humans is inevitable and inexorable

  • First, to critically evaluate the claim that frailty is related to cognitive impairment and, second, to suggest implications of this relationship for understanding dementia prevention and treatment and for the design and analysis of clinical trials

  • It might be that combinations of not just clinical but neuropathological deficits are needed: for example, work from the Honolulu-Asia Aging Study showed that multiple pathologies were associated with dementia, including in people with Alzheimer’s disease [34]

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Summary

Introduction

The aging process has been conceptualized as occurring in small increments as a result of a preference for resources that serve reproduction over those that serve repair With time, such microscopic damage accumulates, leading to clinically detectable deficits, which themselves manifest as tissue, organ, and functional impairment [1]. At least since Gompertz in the 19th century, we have recognized that across the adult lifespan the risk of death increases exponentially with age. One implication of this is that, single-system illness predominates in mortality risk when people are younger, the acceleration in mortality risk beginning partway through the sixth decade reflects that many interacting factors are implicated in causing death [6]. First, to critically evaluate the claim that frailty is related to cognitive impairment and, second, to suggest implications of this relationship for understanding dementia prevention and treatment and for the design and analysis of clinical trials

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