In more than 900 well-characterized community-based older persons without dementia, we found that greater muscle strength was associated with a decreased risk of developing AD. This finding persisted in sensitivity analyses in which we excluded persons who developed AD in the early follow-up years and those with the lowest function at baseline and in models that controlled for BMI, physical activity, pulmonary function, vascular risk factors, vascular diseases and the apolipoprotein E4 allele. Further, muscle strength was associated with the rate of cognitive decline, such that persons with greater strength at baseline exhibited a considerably slower rate of decline. Finally, in an analysis excluding persons dementia or MCI at baseline, muscle strength was associated with the risk of developing MCI, the earliest manifestation of cognitive impairment. Overall, these data show that greater muscle strength is associated with a decreased risk of developing AD and MCI and suggest that a common pathogenesis may underlie loss of strength and cognition in aging.
Although the clinical hallmark of AD is declining cognition, motor signs that frequently accompany AD often precede and predict the clinical diagnosis of AD [1
,47]. Loss of muscle strength and mass also are common in aging, and frailty and BMI are associated with risk of AD [6
]. While measures of frailty and BMI can be obtained inexpensively, they do not inform on the role of muscle mass versus strength with the risk of AD, and recent data suggest that muscle strength is associated with cognition independent of muscle mass [14
]. To date, data on muscle strength and AD is limited. One study reported that grip strength was predictive of cognitive decline in older Mexican Americans [35
], but this study likely included persons with mild dementia at baseline. In another cohort of Catholic Clergy, we found that grip strength was associated with incident AD [17
]. While these findings are important and motivated the current study, grip strength may not fully capture the association of muscle strength (measured more comprehensively) with the risk of AD. We quantified muscle strength in all four extremities as well as in the axial muscles in a large cohort of older persons and found that greater strength was associated with a reduced risk of AD. Further, in analyses of the components of muscle strength, axial muscle strength was associated with the risk of AD even after accounting for grip strength, suggesting that comprehensive assessments of strength may be useful for identifying persons at risk for cognitive impairment. Finally, muscle strength also was associated with a substantially decreased risk of MCI, suggesting a temporal relation whereby impaired strength precedes the development of cognitive impairment in aging. Assessment of muscle strength may have utility for identifying persons at risk for even the earliest manifestation of cognitive impairment and who may benefit most from intervention.
The basis of the association of muscle strength with AD is unknown. Although decreased muscle strength may represent a true risk factor for AD, it is more likely that loss of muscle strength is the result of an underlying disease process that also leads to cognitive decline and clinical AD. For example, muscle plays an important role in energy production and regulation; the mitochondrial theory of aging proposes that damaged mitochondria accumulate over time and these and related energy disruptions are in part responsible for loss of muscle strength and other signs of aging [44
]. The discovery of mitochondrial diseases in aged organisms provides some support for this hypothesis; however, questions remain about its relevance to human aging. It is also important to consider that, while muscle is situated outside the blood brain barrier making it vulnerable to systemic diseases, muscle function is controlled by spinal motor neurons, which reflect supraspinal motor control systems [37
]. Decreased strength may result from disorders of the central nervous system (e.g.
stroke) that may also unmask subclinical AD [46
]. Notably, in this study, the association between strength and AD was unchanged after controlling for vascular risk factors and diseases, suggesting that other factors are important. One such factor is AD pathology, which accumulates slowly over time (before the onset of clinical dementia) and may contribute to decreased strength and cognition. AD pathology frequently occurs in regions that subserve motor function [39
]. Further, the link between executive cognition and movement may suggest that AD pathology even in cognitive regions may contribute to motor decline [45
]. We previously reported an association between AD pathology in the cognitive regions and grip strength [43
]. Future studies are needed to clarify the neurobiologic basis of the association of muscle strength with the risk of AD and the rate of cognitive decline.
Limitations of this study include the selected nature of the cohort, which included participants willing to provide organ donation. Replication of these results in a population-based study is important. Further, although our results suggest that decreased muscle strength precedes the development of cognitive impairment, observational studies cannot directly address the issue of causality. We also cannot rule out the possibility of residual confounding or that a latent variable underlies the association of muscle strength and cognition. However, the study has several strengths, including the use of a large cohort of well-characterized older persons and composite measures of strength and cognition, the uniform classification of AD and MCI, and the ability to examine several potential confounders of the association between strength and AD.