In a cohort of more than 750 well-characterized older persons free of cognitive impairment at baseline, we found that physical frailty was associated with an increased risk of developing MCI, whether defined as the first occurrence of or persistent MCI. This association remained in analyses that controlled for depressive symptoms, disability, vascular risk factors and diseases. Further, physical frailty was associated with an increased rate of decline in global cognition and five specific cognitive systems. These findings demonstrate that a higher level of physical frailty predicts the development of MCI and is associated with an accelerated rate of cognitive decline in older persons. Together with prior studies showing an association between frailty, clinical AD and AD pathology, these data may suggest that physical frailty and cognitive impairment share a common underlying pathogenesis.
Importantly, little is known regarding the factors associated with the development of MCI. Research examining the determinants of MCI is challenging because MCI develops slowly over many years and incidence studies require large samples of persons without cognitive impairment in whom data from multiple years of observation are available. The finding that frailty predicts MCI and cognitive decline has important public health implications. Public policy and aging research are increasingly focusing on the development of strategies to maintain cognitive health and vitality in aging12
. MCI represents the transition state between normality and dementia and may in fact be much more common than AD47
. Moreover, by the time older persons meet criteria for MCI, they are already experiencing cognitive decline, the core feature of AD, and often are accumulating the neuropathologic hallmarks of AD3,5–7
. As new and more effective treatments to prevent or delay the onset of dementia are developed, it will be essential to be able to identify persons who are not yet exhibiting cognitive impairment1–4,33
but who are at increased risk. The current study extends the limited prior work on frailty and cognitive decline33
and suggests that measures of physical frailty may help identify those persons likely to develop cognitive impairment and who are most likely to benefit from interventions to maintain cognitive function.
In this study, the frailty components of grip strength and timed walk were most strongly associated with MCI. Idiopathic decline in motor function is a familiar consequence of aging, with older persons displaying a wide spectrum of loss of muscle strength, muscle bulk, and walking speed34
. These deficits are subsumed under several constructs including physical frailty, sarcopenia, and parkinsonism and there is now considerable evidence showing that idiopathic decline in motor function is common in old age and precedes and predicts a wide range of important health and cognitive outcomes, including death, disability, MCI and AD35–38
. It is possible that specific aspects of motor function have particular prognostic implications.
Although physical frailty may represent a true risk factor for cognitive impairment, it is noteworthy that the biologic basis of the association remains unknown. We suspect that physical frailty, MCI and AD may share an underlying pathogenesis. For example, several factors that are related to physical frailty also are related to cognitive impairment, including inflammatory markers, diabetes, congestive heart failure, and stroke39–42
. Thus, physical frailty may result in part from disorders of the central nervous system (e.g.
, stroke, neurodegenerative diseases), some of which may also unmask subclinical AD. In this study, the association between frailty and MCI persisted in analyses controlling for vascular risk factors and diseases; however, many of our vascular measures were determined by self-report. Given that vascular findings are common and have functional consequences in older persons, further investigation of the influence of vascular factors on cognitive-physical relationships is warranted. Further, although we did not examine this issue directly in this study, it is possible that AD pathology underlies (to some degree) the association of frailty with cognitive impairment. AD pathology is widespread in persons with MCI and even some without cognitive impairment, and this pathology is associated with motor dysfunction as well as cognitive impairment6,7,19,43,44
. We previously reported that AD pathology was associated with physical frailty in older persons with and without dementia from the same cohort; notably, however, AD pathology accounted for only a small percentage of the variance in frailty even in analyses that included persons with clinical dementia19
. Given that it is very likely that non-frail and non-demented persons have AD pathology and that persons with clinically diagnosed cognitive impairment have co-morbid non-AD pathologies46
, other mechanisms must also be important. Some other less well-studied but potential mechanisms may include decreased energy production or metabolic issues and stress. Future studies are needed to explicate the biologic basis of the association between physical frailty and cognitive impairment in old age.
Notably, there is ongoing debate regarding the optimal approach to the classification of MCI and the potential role of disability and/or executive impairment with associated functional limitations48,49
. In this study, persons were diagnosed with MCI if they were determined to have cognitive impairment but did not meet criteria for dementia. The absence of disability was not required, although the absence of disability frequently is cited as a pre-requisite for MCI case finding49
. Thus, the criteria employed for the diagnosis of MCI in this cohort are equivalent to those used for a diagnosis of cognitive impairment, no dementia (i.e., CIND) in some other cohorts24
. It is likely that the use of more restrictive criteria would have captured fewer persons than included in this study; for example, in a study that examined the prevalence and course of amnestic MCI in community-based persons using criteria that required intact instrumental activities of daily living, only about 3–4% of those studied met criteria for MCI48
. It is also possible that more restrictive criteria would have yielded different results. The criteria used here and have been validated in several prior publications using data from this and other cohorts and this definition of MCI is associated with the subsequent development of dementia, particularly AD, and an increased rate of cognitive decline4–7, 24,25
. Further, in this study, we examined the association of frailty with both the first occurrence and persistence of MCI and conducted a series of sensitivity analyses that showed that the association of MCI with frailty was robust and persisted even after controlling for the baseline level of disability or excluding persons with disability either at baseline or at the time of MCI diagnosis.
This study has some limitations, including the selected nature of the cohort, the relatively short duration of follow-up and the need to exclude persons with cognitive impairment (i.e., dementia and MCI) at baseline, as well as those who were not yet eligible for follow-up from analyses, which may have affected the results. Further, participants were from a study that requires older persons to agree to organ donation at death, thereby introducing selection bias. Finally, some of the individual components of frailty, such as fatigue, were assessed fairly crudely and this may have resulted in an underestimation of the association of physical frailty with MCI. However, several factors lend confidence in the findings from this study, including the use of a composite measure of frailty and examination of frailty and incident MCI (first occurrence and persistent) using uniform structured procedures in a large number of well-characterized older persons free of dementia and MCI at baseline and with high rates of annual follow-up.