In this clinical–pathologic study of 165 older persons in the community setting, we found that physical frailty proximate to death was related to level of AD pathology on postmortem examination but was not related to the presence of cerebral infarcts or Lewy body disease. This association was similar in persons with and without dementia and was unchanged even after considering level of physical activity, various physical performance measures, and chronic diseases. These findings raise the possibility that AD pathology may contribute to frailty or that frailty and AD pathology share a common etiopathogenesis.
Physical frailty is common in the elderly, with cross-sectional studies suggesting that approximately 7% of persons older than 65 years are frail, and that the occurrence of frailty increases with age and may exceed 45% after age 85 years.2
Frailty is conceptualized to represent an age-related reduction in physiologic reserve and resistance to stressors and is associated with adverse health outcomes.1,2
While features used to operationalize frailty may be shared by other chronic conditions of aging (i.e., loss of muscle or strength), frailty is common in elders, even after controlling for common chronic health conditions and traditional measures of disability.1,2
The biologic basis of frailty is poorly understood and is thought to be multifactorial and may reflect a subclinical accumulation of common chronic diseases (e.g., cardiovascular and pulmonary disease, diabetes) and their interaction with nonspecific indices (e.g., inflammatory markers) as well as endocrine or metabolic changes, mitochondrial dysfunction, and reduced physical activity.24
In an effort to better understand the biology of frailty, this study examined the extent to which frailty is related to the accumulation of the common age-related brain pathologies, including cerebral infarcts, AD pathology, and Lewy body pathology. In the current study, only AD pathology was related to frailty proximate to death such that a higher level of AD pathology is associated with higher level of frailty (). The association between AD pathology with frailty persisted even after we controlled for other possible factors, such as cardiovascular risk factors and a range of chronic diseases as well as postmortem evidence of infarcts that may contribute to increasing frailty in older persons.25
This study extends findings from a previous clinical study in this same cohort which showed that baseline frailty and rate of increasing frailty were associated an increased risk of subsequent AD and cognitive decline.14
The current postmortem study in those participants, who died, shows that of the three most common age-related neuropathologies, only AD pathology was related to frailty before death. Interestingly, further analyses found that the association of AD pathology with frailty did not differ for persons with and without dementia. Prior work in this26
and other cohorts27,28
found that AD pathology is related to level of cognition among persons without dementia. The results of this current study suggest that one possible explanation for the previously reported clinical association of frailty and incident AD is that frailty may be a noncognitive manifestation of AD pathology that can manifest before dementia. These results should not be surprising. Several indices of motor structure and function, grip strength, gait speed, parkinsonian gait, BMI, and physical activity predict incident AD,5-7,29-31
and some of these measures have been reported to be related to AD pathology.30,32
We speculate that accumulation of AD pathology in brain regions that subserve cognition could affect components of frailty by impairing neural systems involved in the planning, and monitoring of even simple movements. This is suggested by the terminal cognitve decline observed in the elderly without dementia years before death.33-35
Alternatively, AD pathology in cognitive regions might serve as a proxy for AD pathology in other brain regions that regulate components of frailty (e.g., primary motor cortex). Last, frailty and AD pathology may share an underlying etiopathogenesis (e.g., vascular pathology, energy production, stress).36,37
These different mechanisms are not mutually exclusive and underscore the need for further studies of the relationship between AD and frailty.
Our study also has some limitations. Although we were able to control for common neuropathology indices and clinical confounders, postmortem assessment did not directly assess motor brain regions and thus might underestimate the association of frailty with brain pathology. It is possible that a larger study might have shown an association between cerebral infarcts and Lewy body pathology and frailty. The study's main limitation is that the findings are based on a selected cohort that differs in important ways from older persons in the general population in regard to education, socioeconomic status, and lifestyle. It will be important to investigate these findings in more diverse cohorts.
Confidence in these findings is enhanced by several factors. Participants underwent detailed annual structured clinical examinations for up to 10 years, with more than 95% follow-up participation in survivors and a high autopsy rate. Uniform structured procedures were followed with masking of examiners to previously collected data, as well as to postmortem data, reducing the potential for bias. The association of AD pathology and frailty was derived from the same larger cohort in whom we have previously demonstrated a clinical association of frailty and incident AD. Furthermore, analyses controlled for a wide range of potentially confounding variables.