Frailty and dementia: what can the body tell us about the brain?

We have been repeatedly confronted with the failure of tau and amyloid-targeting drugs to meaningfully impact the clinical course of dementia due to Alzheimer’s disease. Although tau and amyloid biomarkers have shown promise in the early diagnosis of Alzheimer’s disease, they will have limited real-world impact until clinically effective, diseasemodifying therapies are attainable. Our attention has increasingly turned to prevention strategies, signaled by the recent Lancet Dementia Commission (Livingston et al., 2020), which reported around 40% of dementias worldwide can be prevented or delayed via a number of potentially modifiable risk factors. Wallace and colleagues (Wallace et al., 2021) retrospectively analyzed post-mortem data and found that frailty, a clinical syndrome of systemic vulnerability, predicted dementia risk in the “oldest-old” that was not accounted for by age or neuropathological burden, supporting the concept that frailty could be a prevention target for dementia. Frailty is widely conceptualized as a state of enhanced vulnerability to stressors and adverse health outcomes resulting from age-related physiological decline. So far, there is no gold standard for how to measure this broad concept. One approach has been to define a frailty phenotype when three out of five phenotypic criteria (low grip strength, low energy, slowed walking speed, low physical activity, and unintentional weight loss) are fulfilled (Fried et al., 2001). A second approach defines frailty more broadly as the accumulation of physical, cognitive, and functional deficits with increasing age, expressed as a frailty index (Mitnitski et al., 2001). The frailty index, employed by Wallace and colleagues’ study, is usually calculated as a ratio of deficits present to the total number of deficits considered and has been shown to indicate the level of frailty, despite different deficits being considered across different studies (Searle et al., 2008). Reassuringly, the two distinct definitions of frailty appear to correlate (Rockwood et al., 2007), and there is converging evidence that frailty could be a proxy measure of aging that can independently predict health outcomes in older patient populations, including cognitive impairment and dementia (Fried et al., 2001; Ma et al., 2020; Petermann-Rocha et al., 2020). In their study, Wallace and colleagues assumed a causal relationship between frailty and dementia to demonstrate the potential impact of frailty prevention on dementia risk. This deserves close consideration, as the relationship does not appear to be a straightforward one. Since the body and brain are generally exposed to the same internal milieu and external environment during an individual’s life course, there are potentially many shared contributing factors between frailty and dementia. Consistent with earlier reports (Gordon and Hubbard, 2020), Wallace and colleagues’ study reported a higher frailty index in women versus men, and as women are also more likely to receive a dementia diagnosis, this suggests that hormonal and/or behavioral and social differences betweenmen and women could be important contributors to both conditions. Other shared etiological factors include increased inflammation (Soysal et al., 2016;Wyss-Coray and Rogers, 2012), poor vascular health (Graciani et al., 2016; Sweeney et al., 2019), and social isolation (Gale et al., 2018; Sommerlad et al., 2019), and there is likely to be interaction between multiple factors. Frailty could therefore be a correlative marker of dementia vulnerability, via the integration of several physiological, and/or social and functional factors that are common to both conditions, without necessarily having a direct causal role. Nonetheless, if there is indeed a causal relationship between frailty and dementia, the direction of causation also needs further investigation, as comorbidities can substantially overlap with the frailty index (Theou et al., 2012). There appears to be overlap between the dementia syndrome and components of the frailty index; over a third of the items in Wallace et al.’s frailty index were functional measures that assessed the participants’ ability to manage activities such as shopping, finances, medicine, transportation, or housework. Impairments in activities of daily life such as these are directly impacted by neurodegenerative processes. They are also necessary for a dementia diagnosis, so will likely have impacted the individual’s functioning for some time before the diagnosis was made. Clinically, it is not uncommon to see patients’ nutritional and subsequent physical health decline alongside worsening cognition, as they gradually lose their International Psychogeriatrics (2021), 33:10, 1001–1003 © International Psychogeriatric Association 2021