Frailty and the risk of cognitive impairment

The phenotypic approach to frailty is widely used 13]. It holds that frailty is best understood as a syndrome. Five features are proposed:
impaired grip strength, exhaustion, slowed gait speed, weight loss, and reduction
in activities. An early report reckoned that the presence of frailty increased the
risk of dementia. This was of interest and has motivated a great deal of work (in
part to address the issue of whether the frailty syndrome should be expanded to include
aspects of cognition and affect) 14].

Given that each of the items that make up the frailty phenotype is recognized as a
risk factor for dementia 8], 15], 16], that they should also convey risk when combined cannot be seen as surprising. In
consequence, here we will evaluate more the relationship between health deficits broadly
construed—as potentially including, but not being restricted to, the five phenotypic
features. That is to say that we will focus on another common view of frailty, which
is that it is a state of increased risk; this risk arises in relation to the number
of health deficits that people have and is mitigated by protective factors 17]–19]. According to this formulation, the reason that as people age they are more likely
to die and that people of the same age have varying risks of death is that, in general,
the risk of death is related to the number of health deficits that people accumulate.
In short, the more health deficits that an individual has, the more likely they are
to die or to experience other adverse health outcomes, including worsening health
status. Not everyone accumulates deficits at the same rate, and it is the people who
have accumulated the most deficits who, at any age, are more likely to die than their
age peers. This then is the basis of frailty 20].

The deficit accumulation approach yields several important features 21]. In cross-sectional evaluations at least from age 50 (and, in some Western studies,
across the life course) in high-, middle-, and low-income countries around the world
21]–24], health deficits accumulate at approximately the same rate (about 3.5 % per year)
and are typically higher in women than in men. Consistent across frailty indexes (FIs),
there appears to be a fixed limit to deficit accumulation. The deficit accumulation
approach operationalizes frailty as the proportion of things wrong (that is, as the
ratio of the number of health deficits present in an individual to the number of health
deficits that were considered). For example, in a database that included 50 items
that met the criteria to be considered health deficits, a person in whom 10 such deficits
were present would have an FI of 10 out of 50, or 0.20. As it turns out, in both community-dwelling
and hospitalized patients (and in intensive care unit series), the 99 % limit to frailty
is 0.7. In short, at least 99 % of people will have FIs of less than 0.7 22], 23], 25]. That is because the closer an individual is to an FI of 0.7, the greater is their
risk of dying.

Health deficit accumulation begins as a consequence of subcellular processes 1]. How subcellular damage scales up to produce clinically detectable health deficits
is a matter of ongoing inquiry 26]. Of note, a key step appears to be captured by subclinical events; for example, even
minor laboratory abnormalities can be detected in otherwise well people, and their
presence increases the risk of adverse health outcomes 27].

Inevitably, the brain is not spared in the aging process. Both cognitive impairment
and dementia, in their various forms, rise with age 28]. By this line of reasoning, it is no coincidence that Alzheimer’s disease incidence
is highest in those who are at least 80 years old because these will be the people
with the greatest number of deficits otherwise. Recent data suggest that deficit accumulation
and cognitive impairment are related, regardless of whether the deficits are considered
as traditional risk factors 10], 29], 30].