Towards a Redefinition of Cognitive Frailty

Abstract

Background: The progressive aging of the population will dramatically increase the burden of dementia related to Alzheimer's disease (AD) and other neurodegenerative disorders in the future. Because of the absence of drugs that can modify the neuropathological substrate of AD, research is focusing on the application of preemptive and disease-modifying strategies in the pre-symptomatic period of the disease. In this perspective, the identification of people with cognitive frailty (CF), i.e., those individuals with higher risk of developing dementia, on solid pathophysiological bases and with clear operational clinical criteria is of paramount importance.

Objective/methods: This hypothesis paper reviews the current definitions of CF, presents and discusses some of their limitations, and proposes a framework for updating and improving the conceptual and operational definition of the CF construct.

Results: The potential for reversibility of CF should be supported by the assessment of amyloid, tau, and neuronal damage biomarkers, especially in younger patients. Physical and cognitive components of frailty should be considered as separate entities, instead of part of a single macro-phenotype. CF should not be limited to the geriatric population, because trajectories of amyloid accumulation are supposed to start earlier than 65 years in AD. Operational criteria are needed to standardize assessment of CF.

Conclusion: Based on the limitations of current CF definitions, we propose a revised one according to a multidimensional subtyping. This new definition might help stratifying CF patients for future trials to explore new lifestyle interventions or disease-modifying pharmacological strategies for AD and dementia.

Keywords: Biomarkers; cognitive frailty; dementia; frailty; mild cognitive impairment; neuropathology; subjective cognitive impairment.

Fig.1

Cognitive frailty and the natural history of Alzheimer’s disease (AD). Here is schematically depicted the natural history of AD with the supposed timing of neuropathological changes in relation to the cognitive decline [59]. The definition of patients with subjective cognitive decline (SCD) and early mild cognitive impairment (MCI) at risk of dementia in the cognitive frailty stage could offer a potential therapeutic window to overcome the limitations of the current unsuccessful therapeutic window of late MCI and early dementia.

Fig.2

The proposed multidimensional clinical construct of cognitive frailty and the parallel neuropathological changes and biomarkers. Clinical construct of cognitive frailty should include subjective cognitive decline (SCD) or mild cognitive impairment (MCI) together with physical frailty and should consider age range and comorbidities (i.e., psychiatric, drug-related and other coexisting conditions). The neuropathological changes and biomarkers, if present, may offer additional prognostic information, e.g., stratifying the risk of conversion to dementia.