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Physical Frailty Could Predict Alzheimer's Disease
  By Alan Mozes
HealthDay Reporter
Wednesday, August 13, 2008; 12:00 AM
WEDNESDAY, Aug. 13 (HealthDay News) -- Physical frailty among the elderly may be linked to early Alzheimer's disease, regardless of whether or not patients develop dementia, new research reveals.
The finding, based on brain autopsies of deceased elderly patients, raises the notion that motor impairment in the elderly is an early symptom of Alzheimer's -- one that appears before mental decline.
It could also turn out to be that frailty and Alzheimer's are not directly linked but stem from a common origin, researchers say.
"What we know is that if you see a very frail person next to somebody not so frail, the very frail person is more likely to have Alzheimer's pathology in their brain when they die," said study lead author Dr. Aron S. Buchman, an associate professor in the department of neurological sciences at Rush University Medical Center in Chicago.
"This is important as we try to wrap our heads around the biology of aging," he added. "Because it turns out that as you get older Alzheimer's pathology, signs of its development are really ubiquitous, even if that doesn't mean that you actually have dementia. So, this finding could alter the way most medical and non-medical people conceptualize Alzheimer's -- as a disease simply of impaired memory and cognition -- while expanding our view of what it actually means to become frail."
Buchman and his colleagues were expected to publish their findings in the Aug. 12 issue ofNeurology.
Prior studies have indicated that about 7 percent of men and women over the age of 65 are frail, meaning they display a significant loss of strength, energy, and agility. That figure rises to 45 percent among people over the age of 85, the researchers said.
In the new study, the Chicago group looked for the presence of the microscopic protein "plaques and tangles" typically associated with Alzheimer's disease in the autopsied brains of 165 male and female study participants.
The autopsies were conducted on Rush patients who had participated in a larger aging and chronic disease study, launched with support from the U.S. National Institute on Aging in 1997. At the time of their deaths, the participants were an average of 88 years old.
While alive, all of the participants had been subject to annual clinical evaluations to assess four markers of frailty: grip strength, time it took to walk eight feet, body mass index (a measure of obesity), and fatigue.
According to the team, patients whose brains showed high levels of Alzheimer's development had been about twice as physically frail as those with low levels of Alzheimer's progression. This was true regardless of whether the patient had experienced dementia or not.
A little more than one-third of the patients had displayed signs of dementia or memory loss prior to their death, the authors noted.
The findings also held up regardless of a patient's physical activity level or disease history.
According to Buchman's group, one previous study that focused on the same group of patients while they were still alive revealed that among those with no cognitive impairment, frailer patients had a higher risk for developing Alzheimer's than those who were less frail.
"So now, we put all this together, and it raises the possibility that Alzheimer's is much more of a public health issue than previously thought, if it turns out that being weak is a sign of its onset," said Buchman. "But, if so, we also now have a clue as to how we can possibly intervene, perhaps by treating motor dysfunction years before people develop dementia, so that they won't develop dementia as early."
Dr. Laurel Coleman, an Augusta, Maine-based geriatrician and member of the Alzheimer's Association's National Board, described the study as "well-done" and "incredibly provocative."
"This study really ties together two very common syndromes in aging --cognitive processes and motor skills -- in ways I have not seen them connected before," she noted. "So, I think this is very important and relevant, because it raises the question of whether frailty could be an early manifestation of Alzheimer's disease. The study doesn't necessarily answer the question, and this is something they now have to go about proving. But already, for me, that idea is a whole new thought that will push me to look at my patients with new eyes." ad_icon
More information
For more on the warning signs of Alzheimer's, visit the Alzheimer's Association.
SOURCES: Aron S. Buchman, M.D., associate professor, department of neurological sciences, Rush University Medical Center, Chicago; Laurel Coleman, M.D., geriatrician, Alzheimer's Association National Board, Augusta, Maine; Aug. 12, 2008,Neurology

Physical frailty in older persons is associated with Alzheimer disease pathology
Neurology Aug 12 2008
Aron S. Buchman, MD, Julie A. Schneider, MD, Sue Leurgans, PhD and David A. Bennett, MD
From Rush Alzheimer's Disease Center (A.S.B., J.A.S., S.L., D.A.B.), Department of Neurological Sciences (A.S.B., J.A.S., S.L., D.A.B.), and Department of Pathology (Neuropathology) (J.A.S.), Rush University Medical Center, Chicago, IL.
Objective: We examined the extent to which physical frailty in older persons is associated with common age-related brain pathology, including cerebral infarcts, Lewy body pathology, and Alzheimer disease (AD) pathology.
Methods: We studied brain autopsies from 165 deceased participants from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study of aging. Physical frailty, based on four components, including grip strength, time to walk 8 feet, body composition, and fatigue, was assessed at annual clinical evaluations. Multiple regression analyses were used to examine the relation of postmortem neuropathologic findings to frailty proximate to death, controlling for age, sex, and education.
Results: The mean age at death was 88.1 years (SD = 5.7 years). The level of AD pathology was associated with frailty proximate to death (Formula = 0.252, SE = 0.077, p = 0.001), accounting for 4% of the variance of physical frailty. Neither cerebral infarcts (Formula = -0.121, SE = 0.115, p = 0.294) nor Lewy body disease pathology (Formula = 0.07, SE = 0.156, p = 0.678) was associated with frailty. These associations were unchanged after controlling for the time interval from last clinical evaluation to autopsy. The association of AD pathology with frailty did not differ by the presence of dementia, and this association was unchanged even after considering potential confounders, including physical activity; parkinsonian signs; pulmonary function; or history of chronic diseases, including vascular risk factors, vascular disease burden, falls, joint pain, or use of antipsychotic or antihypertensive medications.
Conclusion: Physical frailty in old age is associated with Alzheimer disease pathology in older persons with and without dementia.
Abbreviations: AD = Alzheimer disease; BMI = body mass index; FEV1 = forced expiratory volume in 1 second; PEF = peak expiratory flow; VC = vital capacity.
Physical frailty is common in the elderly and associated with adverse health outcomes, but its underlying biology is poorly understood. Although frailty is a heterogeneous syndrome, a number of features, including strength, gait, body composition, and fatigue, are generally accepted as core components of physical frailty.1,2 Cerebral infarcts and Lewy body disease are known to be associated with impaired physical performance.3,4 Furthermore, recent work by several groups suggests that several core components of frailty, including impaired grip strength, slowed gait, and low body mass index (BMI), predict subsequent development of dementia.5-7 These reports suggest that common brain pathology may contribute to physical frailty in the elderly.
We used data from the Rush Memory and Aging Project,8 a longitudinal epidemiologic clinical-pathologic study of chronic conditions of aging, to examine to what extent common age-related brain pathologies, including cerebral infarcts, Lewy body pathology, and Alzheimer disease (AD) pathology, are related to physical frailty before death in older persons with and without dementia.
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 (figure). 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.
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