Frailty is a consequence of advanced aging, a categorization applied to an individual who is greatly physically weakened by the accumulation of cell and tissue damage and its many downstream consequences. Frailty is generally described as some combination of the loss of muscle mass and strength known as sarcopenia, fragility of bones caused by osteoporosis, and a faltering immune system that no longer adequately protects against pathogens, coupled with outcomes such as weakness, exhaustion, and weight loss. The underlying root causes of frailty are also the causes of other age-related conditions, and it is thus expected to find that frail individuals also exhibit a greater incidence of a range of conditions, such as dementia.
How is it that some people can have a brain full of plaques and tangles, yet somehow fend off dementia? Researchers analyzed postmortem data from 456 participants in the Rush Memory and Aging Project (MAP). At their last visit before death, 242 had a diagnosis of possible or probable Alzheimer's disease (AD). Using information gathered from past clinical visits, the researchers calculated a frailty index for each based on a 41-item questionnaire that assessed age-related symptoms, morbidities, and functional deficits. The final score represented a fraction of the total possible deficits. For this cohort, who averaged 89.7 years of age at death, the mean frailty index was 0.42, right at the threshold between moderately and severely frail.
Compared with people who were less frail, those whose frailty was above average were older, likelier to have been diagnosed with AD dementia, and had a higher burden of amyloid-β plaques and tau tangles at autopsy. Thirty-five participants who had not been diagnosed with dementia, but who had a high burden of plaques and tangles, turned out to have low frailty scores. On the other side of the spectrum, 50 who had been diagnosed with dementia but had little AD pathology had the highest frailty indexes. Overall, the findings tied frailty to dementia, and suggested that less frail people are better able to withstand a given amount of AD pathology than their more fragile counterparts.
Could dementia have caused the frailty? The researchers could not rule out reverse causality with their cross-sectional data. However, they did find that the relationship among frailty, pathology, and dementia remained even when they corrected the frailty index for functional deficits that can be caused by dementia, or when they controlled for known dementia risk factors, including stroke and hypertension. The findings suggest that the clinical manifestation of AD depends not just on its neuropathology, but also on the extent of the aging process. People age at different rates, and those who do so more rapidly will not only be more likely to develop AD pathology, but also be more sensitive to it. On a positive note, the findings suggest that slowing the broader process of aging - via changes in lifestyle and/or anti-aging therapeutics - might also prevent dementia.