Around 55 million people are living with dementia worldwide and there are nearly 10 million new cases every year. The impact of dementia on individuals, families, and society can be physical, psychological, social, and economic (WHO, 2022). Medications for treating dementia produce limited clinical benefits (Orrell and Brayne, 2015; Winblad et al., 2016), it is, thus, particularly important to identify potentially modifiable risk factors, which can help predict and/or prevent dementia. The etiology of dementia is multifactorial. A new life-course model reported the twelve potentially modifiable risk factors for dementia, which accounted for around 40% of worldwide dementias: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, low social contact, excessive alcohol consumption, traumatic brain injury, and air pollution (Livingston et al., 2020). At present, the multi-intervention strategy with multiple targets has been proposed to be the most promising way for Alzheimer’s disease (AD) prevention. Thus, we have reason to believe that an integrated indicator, a developing indicator that takes into account all risk factors for dementia, should have an optimal ability for predicting dementia.

Frailty is a multidimensional syndrome reflecting a non-specific state of vulnerability and a multisystem change (Morley et al., 2013). It is an integrated indicator and might serve as a promising target for dementia prevention. A cross-sectional clinicopathological study showed the degree of frailty among people of the same age modified the association between AD pathology and AD, since individuals with even a low level of AD pathology might be at risk for dementia if they had high amounts of frailty (Wallace et al., 2019). Recently, another cross-sectional clinicopathological study suggested that frailty was associated with dementia status independently of neuropathological burden. Preventing severe frailty could avoid 14.2% of dementia cases (Wallace et al., 2021). Besides, the result of a randomized clinical trial confirmed that physical exercise can reverse frailty and improve cognitive function (Tarazona-Santabalbina et al., 2016). In the last decades, although more than forty operational definitions have been proposed about frailty, these can be summarized in four major conceptual models according to constituent elements: physical frailty, cognitive frailty, social frailty, and biopsychosocial frailty. Physical frailty is a medical syndrome that is characterized by diminished strength, endurance, and reduced physiologic function (Morley et al., 2013). Some evidence showed that physical frailty may be closely associated with cognitive impairment (Panza et al., 2015), and one person would be judged to be cognitively frailty if he has both physical frailty and cognitive impairment without dementia (Kelaiditi et al., 2013). Social frailty is a continuum of being at risk of losing, or having lost, social and general resources, activities, or abilities that are important for fulfilling basic social needs (Bunt et al., 2017). Biopsychosocial frailty considers the integral functioning of individuals, and it is a broader concept that covers frailty factors in physical, social, and psychological dimensions (Gobbens et al., 2010; de Vries et al., 2011; Panza et al., 2019).

Though longitudinal studies explored associations between varying concepts of frailty and cognitive disorders [cognitive decline, all-cause dementia (ACD), or AD], the conclusion is largely debated. The present study aims to meta-analyze the relationships of frailty with the risk of developing cognitive disorders based on evaluating the evidence’s credibility.

The present study indicated that non-demented elderly with frailty (including physical, cognitive, social, and biopsychosocial frailty) were at higher risk of developing dementia, though the evidence strength is limited by inconsistency and imprecision. Compared to previous publications (Borges et al., 2019; Bu et al., 2021; Chu et al., 2021), the present study had several advantages: (1) The topic is comprehensive covering all aspects of frailty, including the “biopsychosocial model”; (2) more evidence was incorporated (10 more longitudinal studies); (3) the results were translated based on evidence evaluation, we evaluated the robustness of the evidence for each association and provided clues for further research in this field.

Physical frailty is a condition in which the individual experiences losses in the physical domains of human functioning. We found physical frailty is an important risk factor for cognitive disorders. The underlying mechanisms might be explained by common risk factors shared between physical frailty and cognitive decline. Specifically, common risk factors included brain neuropathology (neurofibrillary tangles, β-amyloid load, nigral neuronal loss, genetic mutations, and cerebral atrophy), hormonal dysregulation (reduced testosterone and insulin resistance), cardiovascular risk (diabetes, dyslipidemia, and hypertension), psychological and environmental factors (depression and nutritional deficiencies) and chronic inflammation (Kelaiditi et al., 2013; Robertson et al., 2013; Gallucci et al., 2018). In studies investigating correlations between frailty and performance in specific cognitive domains in the elderly, physical frailty was associated with memory decline. It is possible that neuropathological effects produced by the above risk factors of physical frailty could affect the hippocampus [associated with memory (Panegyres, 2004)] and result in cognitive disorders. Alterations in hippocampal synaptic function, neuronal membrane properties, and axonal trajectories, which might lead to dementia, have been reported for people with frailty (Bishop et al., 2010). Little work has directly explored mechanisms underlying this link, so experimental evidence is needed to support these possible mediators. Liu and colleagues found that impairment in cognition was associated with the transitions from non-frail to physical frail status (Liu et al., 2021), suggesting that the relationship between physical frailty and cognitive ability may be bi-directional.

Cognitive frailty is a state characterized by cognitive impairment due to physical conditions not the presence of concomitant neurological disease (Kelaiditi et al., 2013). According to our study, cognitive frailty had a stronger predictive validity on dementia than physical frailty. To determine the primary and secondary preventative measures for cognitive frailty, Ruan proposed two subtypes of cognitive frailty based on the severity of cognitive impairment: the reversible and the potentially reversible (the definitions are presented in Box 1; Ruan et al., 2015). Solfrizzi found that the reversible cognitive frailty was a short- and long-term predictor of overall dementia (Solfrizzi et al., 2017b), while no association was revealed between the potentially reversible cognitive frailty and dementia (Solfrizzi et al., 2017a). Our results indicated that cognitive prefrailty is also a vital predictor of cognitive disorders. It may be a useful indicator for identifying early signs of dementia and a promising intervention target for dementia prevention.

Social frailty can be defined as the absence of social resources, social activities, and self-management abilities (Bunt et al., 2017). There are several potential mechanisms between social frailty and cognition at present. First, social stress may affect hormones, immune functioning, and inflammatory processes and induce cognitive decline, social interactions and social support may buffer physiological reactions to stress (Fratiglioni et al., 2000; Cohen, 2004; Agrigoroaei and Lachman, 2011). Second, rich social networks contribute to cognitive function exercise and provide easier access to health information (Berkman et al., 2000; Tsutsumimoto et al., 2019). Third, social frailty was independently associated with poor physical function (Tsutsumimoto et al., 2017), we presume it could lead to cognitive decline through physical frailty.

The three dimensions of frailty (physical, social and psychological) are interrelated rather than independent (Teo et al., 2019), and biopsychosocial frailty fully reflected the multidimensional nature of frailty. However, the risk estimates of cognitive disorders in biopsychosocial frailty individuals were smaller than physical frailty or cognitive frailty in our results. Firstly, follow-up periods of the included studies for biopsychosocial frailty ranged from 5 to 8.5 years and maybe too short to capture overall predictive properties of frailty. Biopsychosocial frailty was evaluated by multidimensional frailty index (FI) in 5 included articles and a previous study showed that frailty based on FI better-predicted dementia over 10 years rather than over 5 years. Items related to health defects for developing multidimensional FI may be partial, leading to smaller risk estimates. Our results showed that multidomain interventions might take an important part in delaying the future appearance of cognitive disorders and secondary occurrence of adverse health-related outcomes, such as disability, hospitalization, and mortality. There have been trials showing that physical exercise can treat frailty and improve cognitive function. The lifestyle interventions and independence for elders study (LIFE)-randomized clinical trial, involving 1,298 participants with cognitive frailty, suggested that physical activity reduced the severity of cognitive frailty compared with a health education program (Liu et al., 2018). Another randomized multicenter control trial proved that physical exercise had benefits for cognitive status among physical pre-frail/frail patients with mild cognitive impairment or dementia (Casas-Herrero et al., 2019). Furthermore, the findings from another randomized trial ascertained a supervised-facility multicomponent exercise program can reverse physical frailty and improve cognitive function (Tarazona-Santabalbina et al., 2016). Physical exercise should be regarded as a vital component of multidomain interventions. Better results may be produced if physical exercise is combined with interventions in other areas.

Our results suggested a frail state may indicate the onset of cognitive decline; however, the results are subject to some limitations in practical application. First, heterogeneity of frailty diagnostic criteria and diagnostic methods of the outcome. Diverse diagnostic criteria of frailty had been used now. Physical frailty is diagnosed as physical FI ≥ 0.25 or conforms to the standard of frailty phenotype, while biopsychosocial frailty is evaluated based on multidimensional FI in most cases. Nevertheless, the items included in FI and diagnostic criteria of social and cognitive frailty are ambiguous. Second, the threshold for assessing frailty or non-frailty varied from study to study, which could significantly affect the proportions classified as frail or not. However, we cannot investigate thresholds and potential impacts because the studies used diverse frailty scales and evaluation criteria. Third, participants from organizations such as medical centers tended to have more risk factors of cognitive decline than community residents. That may decrease the representation of the total population. Fourth, the length of follow-up included in meta-analysis ranged from 2 to 15 years, insufficient follow-up time in some studies may reduce risk estimates of cognitive disorders.

Based on the credibility of our meta-analyses, we propose several suggestions for future research. Firstly, developing authoritative screening scales with higher sensitivity and specificity for cognitive frailty and biopsychosocial frailty, and controlling confounding factors may sufficiently help reduce inconsistency. Furthermore, expanding sample size or random sampling from community residents could promote the generalizability of the conclusion. Frailty and cognitive changes should be measured simultaneously in longitudinal studies with adequate follow-up to test for reverse causation or lead-lag effects.

In conclusion, the present study suggested that frailty is significant to help identify populations at high risk of cognitive disorders. Frail elderly should be regarded as the primary target of resource allocation in the prevention and treatment of dementia.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

WX: conceptualization and design of the study, and revision of the manuscript. C-YG: collection and analysis of the data, drafting and revision of the manuscript, and preparation of all the figures. C-CT: collection of the data. ZS and LT: revision of the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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