Is There a Sex-Frailty Paradox in Dementia?

Introduction

Humans age at different rates due to a complex interplay between heritable factors and environmental exposures. These differences exist at the microscopic level in the hallmarks of ageing (1) and, too, at a level more readily perceivable as variability in health, function and vulnerability (2). This latter expression of ageing has been conceptualised as frailty (3, 4), which increases risk of adverse health outcomes and death at any chronological age (5). Frailty is also intimately related to later-life dementia as it both increases the risk of dementia and worsens following its onset. There is a growing understanding of sex differences in both frailty and dementia. Here, we briefly review those differences before considering whether sex influences the relationship between frailty and dementia.

Frailty and dementia

Epidemiological evidence supporting a causal role of frailty in dementia development continues to accumulate. Investigations using the population-based UK Biobank cohort have recently reported a substantially higher risk for incident dementia among people with frailty regardless of whether the phenotype or deficit accumulation model was applied (6, 7). Similar associations have been observed in other cohort studies, including the Rush Memory and Aging Project (8), the National Alzheimer's Coordinating Center database (9), and the English Longitudinal Study of Ageing (10). That these findings appear robust to challenges of bias and confounding, and that associations remain following adjustment for chronological age, suggests that dementia, in many cases, is a complex outcome of ageing. This viewpoint is supported by parallel evidence indicating that changes in the hallmarks of ageing correlate with susceptibility to neurodegenerative diseases (11).

Although mechanisms underlying the frailty-cognition association are still under investigation and relationships are complex (12), some progress has been made in recent years. One possibility is that frailty causes an acceleration of age-related neuropathologies. In support, neuroimaging studies reliably link frailty with detrimental brain characteristics, such as lower grey matter volume (13) and markers of cerebrovascular disease (13, 14, 15), and findings from a clinical-pathologic study showed that at autopsy people who had higher frailty prior to death had a higher burden of Alzheimer's neuropathology (16). Another possibility is that the reduced physiological reserve characteristic of frailty increases the likelihood of dementia expression from a smaller neuropathological burden. In support, recent investigations have reported a weakening in the relationship between traditional dementia risk factors, such as neuropathological markers and polygenic dementia risk, and the presence or occurrence of dementia (6, 16, 17). These observations may be due to a high degree of frailty partially saturating dementia risk, requiring little (or no) contribution from other risk factors for dementia to occur (18).

It is important to consider, too, how dementia may worsen frailty. In one study that measured physical functioning using a modified 9-item Physical Performance Test (incorporating assessments of mobility, balance and strength), participants with dementia declined more rapidly than those who remained cognitively normal across the 5-year observation period, with even faster declines among those in the later stages of dementia (19). Such physical declines would increase the likelihood of being classified as frail under the phenotype model and be reflected as a higher degree of frailty under the deficit accumulation model. In support, studies using different methods of frailty assessment have reported worse frailty trajectories among people with cognitive impairment/dementia (20, 21).

The sex-frailty paradox and dementia

It is well established that from midlife onwards women tend to have more health conditions, greater levels of disability, and rate their own health more poorly than men (22). A meta-analysis of five large studies of community-dwelling older adults found that in every assessed age group (from 65–69 years to 90–94 years) women tended to have higher frailty index scores than men (23). Notably, the size of these mean differences in frailty index scores increased with advancing age, rising from 0.02 in the youngest age group to 0.06 in the oldest age group, corresponding to 0.8 and 2.4 additional health and functional deficits, on average. This trend is supported by more recent meta-analytic data that reported a higher prevalence of frailty in women than in men regardless of whether the deficit accumulation or phenotype model was applied (24). Despite being ‘more frail', women live longer than men. Globally, in 2019, life expectancy at birth of females was approximately five years longer than that of males (25). This ‘sex-frailty paradox' has been well described in modern Western and non-Western population studies (23).

Sex differences also exist in dementia. A recent meta-analysis of 205 studies and almost one million individuals from 43 countries reported higher incidences of Alzheimer's dementia in women and vascular dementia in men, although statistically significant differences were observed only in the oldest age groups (26). Risk factors for dementia also differ in prevalence and impact between men and women (27). For example, men have, historically, tended to have higher educational attainment and consequently more cognitive reserve than women, and carrying an apolipoprotein E ε4 allele increases risk of Alzheimer's disease by considerably more in women than men. Overall, in the search for traits that may impact the relevance of frailty to dementia prevention, sex appears a viable candidate.

The sex-frailty paradox suggests that women tolerate the deleterious effects of frailty better than men (23). However, it is not yet clear whether sex differences exist in the impact of frailty on other outcomes, such as later-life dementia. Two recent studies investigating the links between frailty and incident dementia in the UK Biobank cohort reported consistent results regarding sex despite applying different models of frailty (6, 7). The earlier study found the presence of frailty (phenotype) was associated with a larger increase in dementia risk in women than in men (HRs 2.28 and 1.64) (7). The later found each 0.1 increase in frailty index scores (deficit accumulation) was also associated with a larger increase in dementia risk in women (HRs 1.63 and 1.59) (6). Even so, in both studies, these sex-related differences were tested using interaction terms and were not statistically significant. Other studies have also reported sex-stratified associations of frailty and incident dementia without the emergence of clear trends (9, 28, 29).

Conclusions

Here we briefly reviewed the evolving evidence implicating frailty in the development of dementia, as well as sex differences in both conditions. Irrespective of the frailty model used (deficit accumulation or phenotype), frailty is reliably observed to be more common in women than in men, but there is currently no evidence to indicate that women cope better with it in terms of its impact on risk of dementia. Since there does not appear to be a sex-frailty paradox in dementia, we hypothesise that both sexes are likely to benefit from interventions aimed at preventing or reducing frailty to mitigate dementia risk.

Conflict of interest:

The authors have nothing to disclose.