Shared mechanisms for cognitive impairment and physical frailty: A model for complex systems

Abstract

Introduction We describe findings from a large study that provide empirical support for the emerging construct of cognitive frailty and put forth a theoretical framework that may advance the future study of complex aging conditions. While cognitive impairment and physical frailty have long been studied as separate constructs, recent studies suggest they share common etiologies. We aimed to create a population predictive model to gain an understanding of the underlying biological mechanisms for the relationship between physical frailty and cognitive impairment. Methods Data were obtained from the longitudinal “ Invecchaiare in Chianti” (Aging in Chianti, InCHIANTI Study) with a representative sample (n = 1453) of older adults from two small towns in Tuscany, Italy. Our previous work informed the candidate 132 single nucleotide polymorphisms (SNPs) and 155 protein biomarkers we tested in association with clinical outcomes using a tree boosting, machine learning (ML) technique for supervised learning analysis. Results We developed two highly accurate predictive models, with a Model I area under the curve (AUC) of 0.88 (95% confidence interval [CI] 0.83‐0.90) and a Model II AUC of 0.86 (95% CI 0.80‐0.90). These models indicate cognitive frailty is driven by dysregulation across multiple cellular processes including genetic alterations, nutrient and lipid metabolism, and elevated levels of circulating pro‐inflammatory proteins. Discussion While our results establish a foundation for understanding the underlying biological mechanisms for the relationship between cognitive decline and physical frailty, further examination of the molecular pathways associated with our predictive biomarkers is warranted. Our framework is in alignment with other proposed biological underpinnings of Alzheimer's disease such as genetic alterations, immune system dysfunction, and neuroinflammation.

An update on cognitive frailty: Its definition, impact, associated factors and underlying mechanisms, and interventions

“…Among 5076 subjects screened for reversible cognitive frailty, the prevalence of reversible cognitive frailty was shown to be 19.9% (n = 1008), with older age, female, higher education and marital status (single) shown to be associated with reversible cognitive frailty. 46 The model of "potentially reversible" cognitive frailty has been investigated in population-based studies, 29,[50][51][52][53][54][55][56][57][58] in a memory clinic population, 59 and in a case-control study, 60 as well as in populations included in randomized control trials, [61][62][63] where the prevalence of "potentially reversible" cognitive frailty ranges from 6.3% to 59.1%. Most of the studies that focused on the "potentially reversible" cognitive frailty model used the modified CHS criteria, with a few studies shown to use the FRAIL scale 46,55,56 or Edmonton Frailty Scale 60 to assess physical frailty.…”

“…16 In another study, omics analysis with machine learning statistical approaches suggested that cognitive frailty is driven by multisystem dysfunction across multiple cellular processes, including genetic alterations, nutrient and lipid metabolism, and elevated levels of circulating proinflammatory proteins. 54…”

Cognitive Frailty: An Update

“…Considering that lipids are a major component (70%) of the composition of the human brain, variations in these compounds could potentially be used as biomarkers of cognitive problems. In recent research, Sargent et al ( 2020 ) found that low levels of vitamin E alpha tocopherol, omega-6 and 3 and albumin were associated with CF. In addition, these researchers observed a second pattern of association characterized by a low level of trans fats, as indicated by measuring low and high density lipoproteins (LDL and HDL).…”

Relationships Among Cognitive Function, Frailty, and Health Outcome in Community-Dwelling Older Adults

“…In addition, based on data from the Canadian Study of Health and Aging, Song et al (2014) found that the incidence rate of cognitive impairment increased exponentially with the increase of frailty index, and frailty is an independent risk factor for cognitive impairment. Cognitive impairment is related to frailty, and both have common biological mechanisms, including genetic alternations, immune system dysfunction, and neuroinflammation (Sargent et al, 2020).…”